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Critical Reviews in Oncology/hematology May 2018Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids.... (Review)
Review
Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Humans; Lenalidomide; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Thalidomide; Treatment Outcome
PubMed: 29650268
DOI: 10.1016/j.critrevonc.2018.02.008 -
Clinical Therapeutics Mar 2018New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in... (Comparative Study)
Comparative Study Meta-Analysis
PURPOSE
New therapies, including daratumumab plus lenalidomide plus dexamethasone (DRd) and daratumumab plus bortezomib plus dexamethasone (DVd), have recently been approved in the United States for patients with multiple myeloma (MM) who have received at least 1 prior line of therapy. However, few treatments have been compared in head-to-head clinical trials to determine the most efficacious therapy. In an update of the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) trial, median progression-free survival (PFS) for DRd was not reached; the hazard ratio compared with Rd was 0.41. In an update of the CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trial, median PFS for DVd was 16.7 months, compared with 7.1 months for Vd with a PFS hazard ratio of 0.31. A systematic literature review and network meta-analysis (NMA) was performed to estimate the relative efficacy of treatments for previously treated patients with MM.
METHODS
A systematic search of MEDLINE, EMBASE, BioSciences Information Service, and the Cochrane Library databases was conducted from initiation to September 2016. Abstracts published by international congresses (2014-2016) and bibliographies of pertinent systematic reviews and meta-analyses were also searched. Eligible studies consisted of randomized controlled trials (RCTs) or long-term follow-up studies with >1 treatment arm assessing the efficacy or safety of MM therapies. An NMA was conducted by using Bayesian fixed effect mixed-treatment comparisons. Outcomes considered were hazard ratios for PFS and odds ratios for overall response rate (ORR).
FINDINGS
In total, 108 articles reporting 27 RCTs were included in the NMA. Data formed 2 evidence networks: RCTs with DRd and RCTs with DVd. Primary analysis of PFS found that DRd and DVd had a higher probability of being the best treatments (probability, 0.997 and 0.999, respectively) and had the lowest risk of progression or death than other treatments approved by the US Food and Drug Administration for the treatment of MM. Results from sensitivity analyses using time to progression as a proxy for missing PFS data were consistent. DRd and DVd also showed improved ORR compared with other treatments. Subgroup analyses of PFS in patients treated with only 1 prior therapy were like the results of the primary analyses.
IMPLICATIONS
This NMA provides comparative efficacy for MM treatments not studied in head-to-head RCTs. The NMA suggests that, compared with other approved MM treatments in the United States, DRd and DVd have a higher probability of providing the longest PFS in patients who have received at least 1 prior therapy and in patients who have received only 1 prior therapy.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bortezomib; Dexamethasone; Humans; Lenalidomide; Multiple Myeloma; Network Meta-Analysis; Randomized Controlled Trials as Topic
PubMed: 29500140
DOI: 10.1016/j.clinthera.2018.01.014 -
JAMA Oncology Mar 2018The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction.
OBJECTIVE
To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT.
DATA SOURCES
We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: "myeloma" combined with "autologous," "transplant," "myeloablative," or "stem cell."
STUDY SELECTION
Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis.
DATA EXTRACTION AND SYNTHESIS
For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs.
MAIN OUTCOMES AND MEASURES
The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes.
RESULTS
A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%).
CONCLUSIONS AND RELEVANCE
The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase III as Topic; Dexamethasone; Drugs, Investigational; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lenalidomide; Multiple Myeloma; Neoadjuvant Therapy; Network Meta-Analysis; Prognosis; Randomized Controlled Trials as Topic; Remission Induction; Transplantation, Autologous; Treatment Outcome
PubMed: 29302684
DOI: 10.1001/jamaoncol.2017.4600 -
BMJ Open Oct 2017To assess the effectiveness of sitagliptin compared to sulfonylureas as add-on to metformin in adults with type 2 diabetes mellitus from both randomised controlled... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
To assess the effectiveness of sitagliptin compared to sulfonylureas as add-on to metformin in adults with type 2 diabetes mellitus from both randomised controlled trials (RCTs) and 'real-world' non-randomised studies.
METHODS AND ANALYSES
We conducted a systematic review of EMBASE, MEDLINE, CENTRAL and grey literature for RCTs and non-randomised studies. We reported outcomes relating to change in HbA1c, fasting glucose, weight, blood pressure and lipids from baseline and need for treatment change. No study investigating macrovascular and microvascular diabetes complications was found. Meta-analysis was used where studies were sufficiently homogenous.
RESULTS
Seven RCTs and five non-randomised studies were eligible for inclusion from 1335 articles retrieved. Meta-analysis of three homogenous RCTs revealed a statistically significant decrease in weight with sitagliptin when compared to sulfonylureas (weighted mean difference (WMD) -2.05 kg; 95% CI -2.38 to -1.71); however, a similar change from baseline in HbA1c (WMD 0.05; 95% CI -0.03 to 0.12), fasting glucose (WMD 0.11; 95% CI -0.08 to -0.29), blood pressure, lipids and the proportion achieving HbA1c <7% by study end (OR 0.98; 95% CI 0.85 to 1.13) was observed.Non-randomised studies identified consisted of four prospective and one retrospective cohort study. Three of these five studies were of moderate/high quality, and results though less precise suggested similar real-world comparative glycaemic and weight effectiveness for both treatments. Data from two cohort studies suggested that treatment change (HR 0.65; 95% CI 0.57 to 0.73) and insulin initiation (HR 0.76; 95% CI 0.65 to 0.90) were less likely among those prescribed sitagliptin; however, inadequate reporting of HbA1c at time of treatment change made interpreting results challenging.
CONCLUSION
Sitagliptin users experienced modest weight loss compared to gain with sulfonylureas; however, this difference was around 2 kg, which may not be of major clinical significance for most individuals. Similar change was observed across most other effectiveness outcomes reported. Further studies are needed to address longer-term effectiveness outcomes for sitagliptin compared to sulfonylureas as add-on to metformin.
PROSPERO REGISTRATION NUMBER
CRD42016033983.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Outcome Assessment, Health Care; Sitagliptin Phosphate; Sulfonylurea Compounds; Weight Loss; Young Adult
PubMed: 29084794
DOI: 10.1136/bmjopen-2017-017260 -
Daru : Journal of Faculty of Pharmacy,... Oct 2017Diabetes is one of the most common chronic and costly diseases worldwide and type 2 diabetes is the most common type which accounts for about 90% of cases with diabetes.... (Comparative Study)
Comparative Study Review
BACKGROUND
Diabetes is one of the most common chronic and costly diseases worldwide and type 2 diabetes is the most common type which accounts for about 90% of cases with diabetes. New medication-therapy regimens such as those containing linagliptin alone or in combination with other medications (within the category of DDP-4 inhibitors) must be evaluated in terms of efficacy and compared with other currently used drugs and then enter the medication list of the country. Hence, this study aimed to compare the clinical efficacy of the two drugs, i.e. linagliptin and sitagliptin, in patients with type 2 diabetes.
METHODS
A systematic review was conducted to identify all clinical trials published by 2015 which compared the two drugs in patients with type 2 diabetes. Using keywords such as "linagliptin", "type 2 diabetes mellitus", "sitagliptin" and related combinations, we searched databases including Scopus, PubMed, and Web of Science. The quality of the selected studies was evaluated using the Jadad score. Considering primary and secondary outcomes extracted from the reviewed studies, a network meta-analysis was used to conduct a systematic comparison between the two studied drugs.
RESULTS
This network meta-analysis included 32 studies (Linagliptin vs PLB: n = 8, Sitagliptin vs PLB: n = 13, Linagliptin + MET vs PLB + MET: n = 4, and Sitagliptin + MET vs PLB + MET: n = 7) and a total of 13,747 patients. The results showed no significant difference between linagliptin and sitagliptin in terms of key efficacy and safety outcomes such as HbA1c changes from baseline, body weight change from baseline, percentage of patients achieving HbA1c <7, and percentage of patients experiencing hypoglycemic events (p > 0.05). The results showed that the efficacy of the two drug regimens was the same.
CONCLUSIONS
Based on the results, there was no significant difference between the two drugs, i.e. linagliptin and sitagliptin, in terms of efficacy; in other words, the efficacy of the two drugs was the same. Therefore, the use of these two drugs depends on their availability and cost. Graphical abstract of the network meta-analysis performed to evaluate the alternatives under the study.
Topics: Aged; Aged, 80 and over; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Network Meta-Analysis; Sitagliptin Phosphate; Treatment Outcome
PubMed: 29070077
DOI: 10.1186/s40199-017-0189-6 -
Medicine Sep 2017The aim of this systematic review was to evaluate the efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The aim of this systematic review was to evaluate the efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2 diabetes and provide reference basis for rational use of clinical drugs.
METHODS
Several databases were searched, including Web of science, PubMed, Cochrane library, CNKI, and Wanfang database. Only randomized controlled trials (RCTs) of liraglutide versus sitagliptin both in combination with metformin up to 31 August 2016 were included. Data were extracted independently by 2 reviewers, and a fixed or random effects model were used to analyze outcomes that were expressed as odds ratio (OR) or mean difference (MD) and 95% confidence intervals (95% CIs) for different situations.
RESULTS
Five RCTs involving 1440 participants were included. Compared with sitagliptin combination with metformin group, participants' treatment with 1.2 mg and 1.8 mg liraglutide with metformin could significantly lower the level of glycosylated hemoglobin (HbA1c) (P < .00001, MD = -0.35, 95% CI -0.51 to -0.20). Moreover, patients with 1.8 mg liraglutide group had significant body weight loss (P < .00001, MD = -1.12, 95% CI -1.54 to -0.70). However, there were no obvious differences in cutting down the systolic blood pressure and diastolic blood pressure between liraglutide-metformin and sitagliptin-metformin groups. The incidence of gastrointestinal problems was significantly higher than sitagliptin with metformin groups.
CONCLUSION
The results of this meta-analysis indicated that Liraglutide added on to metformin therapy could significantly lower the level of HbA1c and increase body weight loss. Meanwhile, the adverse reactions such as gastrointestinal problems were common in the liraglutide treatment group. Thus, this will provide an important reference for the treatment of patients with type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Treatment Outcome
PubMed: 28953663
DOI: 10.1097/MD.0000000000008161 -
PloS One 2017Bortezomib is recently studied as a novel agent in indolent lymphoma. The optimal schedule of bortezomib used in indolent lymphoma is still uncertain. (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Bortezomib is recently studied as a novel agent in indolent lymphoma. The optimal schedule of bortezomib used in indolent lymphoma is still uncertain.
METHODS
We did a systematic review and meta-analysis of the clinical trials comparing the efficacy and toxicity of the weekly and biweekly schedules of bortezomib in patients with indolent lymphoma. We searched Pubmed, Cochrane Library and Emabase from inception to July 29, 2016. The primary outcome was the overall response rate including the complete response rate and the partial response rate. The secondary outcomes were the proportions of patients in each group experiencing the adverse events including the neutropathy, fatigue, diarrhea, nausea and neutropenia.
FINDINGS
After final screening, six trials were considered eligible for analysis. The results showed that the overall response rate of biweekly schedule was higher than that of weekly schedule in indolent lymphoma (OR 1.691;95%CI 1.02-2.80). Furthermore, there were no significant differences between the two schedules of bortezomib for the main adverse events.
INTERPRETATION
The biweekly schedule of bortezomib was more effective than the weekly schedule in indolent lymphoma, with similar proportion of toxicities.
Topics: Aged; Antineoplastic Agents; Bortezomib; Clinical Trials as Topic; Drug Administration Schedule; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Survival Analysis; Treatment Outcome
PubMed: 28531181
DOI: 10.1371/journal.pone.0177950 -
Paediatric Drugs Jun 2017A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing... (Review)
Review
Safety, Tolerability and Efficacy of Drugs for Treating Behavioural Insomnia in Children with Attention-Deficit/Hyperactivity Disorder: A Systematic Review with Methodological Quality Assessment.
OBJECTIVE
A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing but also impact family functioning. Management of sleep problems is consequently an important aspect of overall ADHD management in paediatric patients. Although some drugs are being used off-label for the management of paediatric insomnia, there is scant clinical evidence supporting their use. Our aim was to identify and assess the quality of published studies reporting the safety, tolerability and efficacy of drugs used for treating behavioural insomnia in children with ADHD.
METHODS
After an initial screen to determine which drugs were most commonly used, we conducted a systematic review of English-language publications from searches of PubMed, EMBASE, PsycINFO and two trial register databases to February 2017, using keywords 'clonidine', 'melatonin', 'zolpidem', 'eszopiclone', 'L-theanine', 'guanfacine', 'ADHD', 'sleep disorder' and 'children'. For quality assessment of included studies, we used the CONSORT checklist for randomised control trials (RCTs) and the Downs and Black checklist for non-RCTs.
RESULTS
Twelve studies were included. Two case series for clonidine, two RCTs and four observational studies for melatonin and one RCT each for zolpidem, eszopiclone, L-theanine and guanfacine. Of the 12 included studies, only one on eszopiclone scored excellent for quality. The quality of the rest of the studies varied from moderate to low. For clonidine, melatonin and L-theanine, improvements in sleep-onset latency and total sleep duration were reported; however, zolpidem, eszopiclone and guanfacine failed to show any improvement when compared with placebo. Clonidine, melatonin, L-theanine, eszopiclone and guanfacine were well tolerated with mild to moderate adverse events; zolpidem was associated with neuropsychiatric adverse effects.
CONCLUSION
There is generally poor evidence for prescribing drugs for behavioural insomnia in children with ADHD. Further controlled studies are warranted.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Clonidine; Eszopiclone; Glutamates; Guanfacine; Humans; Melatonin; Observational Studies as Topic; Pyridines; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 28391425
DOI: 10.1007/s40272-017-0224-6 -
Clinical Infectious Diseases : An... Jun 2017Evidence-based recommendations for treating persons having presumed latent tuberculosis (LTBI) after contact to infectious multidrug-resistant (MDR) tuberculosis (TB)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND.
Evidence-based recommendations for treating persons having presumed latent tuberculosis (LTBI) after contact to infectious multidrug-resistant (MDR) tuberculosis (TB) are lacking because published data consist of small observational studies. Tuberculosis incidence in persons treated for latent MDR -TB infection is unknown.
METHODS.
We conducted a systematic review of studies published 1 January 1994-31 December 2014 to analyze TB incidence, treatment completion and discontinuation, and cost-effectiveness. We considered contacts with LTBI effectively treated if they were on ≥1 medication to which their MDR-TB strain was likely susceptible. We selected studies that compared treatment vs nontreatment outcomes and performed a meta-analysis to estimate the relative risk of TB incidence and its 95% confidence interval.
RESULTS.
We abstracted data from 21 articles that met inclusion criteria. Six articles presented outcomes for contacts who were treated compared with those not treated for MDR-LTBI; 10 presented outcomes only for treated contacts, and 5 presented outcomes only for untreated contacts. The estimated MDR-TB incidence reduction was 90% (9%-99%) using data from 5 comparison studies. We also found high treatment discontinuation rates due to adverse effects in persons taking pyrazinamide-containing regimens. Cost-effectiveness was greatest using a fluoroquinolone/ethambutol combination regimen.
CONCLUSIONS.
Few studies met inclusion criteria, therefore results should be cautiously interpreted. We found a reduced risk of TB incidence with treatment for MDR-LTBI, suggesting effectiveness in prevention of progression to MDR-TB, and confirmed cost-effectiveness. However, we found that pyrazinamide-containing MDR-LTBI regimens often resulted in treatment discontinuation due to adverse effects.
Topics: Antitubercular Agents; Cost-Benefit Analysis; Disease Progression; Drug Resistance, Multiple, Bacterial; Ethambutol; Fluoroquinolones; Humans; Latent Tuberculosis; Pyrazinamide; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 28329197
DOI: 10.1093/cid/cix208 -
The Cochrane Database of Systematic... Feb 2017Kidney transplantation is the preferred form of kidney replacement therapy for patients with end-stage kidney disease (ESKD) and is often complicated by worsening or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Kidney transplantation is the preferred form of kidney replacement therapy for patients with end-stage kidney disease (ESKD) and is often complicated by worsening or new-onset diabetes. Management of hyperglycaemia is important to reduce post-transplant and diabetes-related complications. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown.
OBJECTIVES
To evaluate the efficacy and safety of pharmacological interventions for lowering glucose levels in patients who have undergone kidney transplantation and have diabetes.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Specialised Register to 15 April 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI).
MAIN RESULTS
We included seven studies that involved a total of 399 kidney transplant recipients. All included studies had observed heterogeneity in the patient population, interventions and measured outcomes or missing data (which was unavailable despite correspondence with authors). Many studies had incompletely reported methodology preventing meta-analysis and leading to low confidence in treatment estimates.Three studies with 241 kidney transplant recipients examined the use of more intensive compared to less intensive insulin therapy in kidney transplant recipients with pre-existing type 1 or 2 diabetes. Evidence for the effects of more intensive compared to less intensive insulin therapy on transplant graft survival, HbA1c, fasting blood glucose, all cause mortality and adverse effects including hypoglycaemia was of very low quality. More intensive versus less intensive insulin therapy resulted in no difference in transplant or graft survival over three to five years in one study while another study showed that more intensive versus less intensive insulin therapy resulted in more rejection events over the three year follow-up (11 events in total; 9 in the more intensive group, P = 0.01). One study showed that more intensive insulin therapy resulted in a lower mean HbA1c (10 ± 0.8% versus 13 ± 0.9%) and lower fasting blood glucose (7.22 ± 0.5 mmol/L versus 13.44 ± 1.22 mmol/L) at 13 months compared with standard insulin therapy. Another study showed no difference between more intensive compared to less intensive insulin therapy on all-cause mortality over a five year follow-up period. All studies showed either an increased frequency of hypoglycaemia or severe hypoglycaemia episodes.Three studies with a total of 115 transplant recipients examined the use of DPP4 inhibitors for new-onset diabetes after transplantation. Evidence for the treatment effect of DPP4 inhibitors on transplant or graft survival, HbA1c and fasting blood glucose levels, all cause mortality, and adverse events including hypoglycaemia was of low quality. One study comparing vildagliptin to placebo and another comparing sitagliptin to placebo showed no difference in transplant or graft survival over two to four months of follow-up. One study comparing vildagliptin to placebo showed no significant change in estimated glomerular filtration rate from baseline (1.9 ± 10.3 mL/min/1.73 m, P = 0.48 and 2.1 ± 6.1 mL/min/1.73 m, P = 0.22) and no deaths, in either treatment group over three months of follow-up. One study comparing vildagliptin to placebo showed a lower HbA1c level (mean ± SD) (6.3 ± 0.5% versus versus 6.7 ± 0.6%, P = 0.03) and trend towards a greater lowering of fasting blood glucose (-0.91 ± -0.92 mmol/L versus vs -0.19 ± 1.16 mmol/L, P = 0.08) with vildagliptin. One study comparing sitagliptin to insulin glargine showed an equivalent lowering of HbA1c (-0.6 ± 0.5% versus -0.6 ± 0.6%, P = NS) and fasting blood glucose (4.92 ± 1.42 versus 4.76 ± 1.09 mmol/L, P = NS) with sitagliptin. For the outcome of hypoglycaemia, one study comparing vildagliptin to placebo reported no episodes of hypoglycaemia, one study comparing sitagliptin to insulin glargine reported fewer episodes of hypoglycaemia with sitagliptin (3/28 patients; 10.7% versus 5/28; 17.9%) and one cross-over study of sitagliptin and placebo reported two episodes of asymptomatic moderate hypoglycaemia (2 to 3.9 mmol/L) when sitagliptin was administered with glipizide. All three studies reported no drug interactions between DPP4 inhibitors and the immunosuppressive agents taken.Evidence for the treatment effect of pioglitazone for treating pre-existing diabetes was of low quality. One study with 62 transplant recipients compared the use of pioglitazone with insulin to insulin alone for treating pre-existing diabetes. Pioglitazone resulted in a lower HbA1c level (mean ± SD) (-1.21 ± 1.2 versus 0.39 ± 1%, P < 0.001) but had no effects on fasting blood glucose (6.58 ± 2.71 versus 7.28 ± 2.78 mmol/L, P = 0.14 ), and change in creatinine (3.54 ± 15.03 versus 10.61 ± 18.56 mmol/L, P = 0.53) and minimal adverse effects (no episodes of hypoglycaemia, three dropped out due to mild to moderate lower extremity oedema, cyclosporin levels were not affected).
AUTHORS' CONCLUSIONS
Evidence concerning the efficacy and safety of glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients is limited. Existing studies examine more intensive versus less intensive insulin therapy, and the use of DPP4 inhibitors and pioglitazone. The safety and efficacy of more intensive compared to less intensive insulin therapy is very uncertain and the safety and efficacy of DPP4 inhibitors and pioglitazone is uncertain, due to data being limited and of poor quality. Additional RCTs are required to clarify the safety and efficacy of current glucose-lowering agents for kidney transplant recipients with diabetes.
Topics: Adamantane; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Glycated Hemoglobin; Graft Survival; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kidney Transplantation; Nitriles; Pioglitazone; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Thiazolidinediones; Vildagliptin
PubMed: 28238223
DOI: 10.1002/14651858.CD009966.pub2