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BMJ Open Jan 2017To evaluate the effect of pioglitazone in people with insulin resistance, pre-diabetes and type 2 diabetes. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To evaluate the effect of pioglitazone in people with insulin resistance, pre-diabetes and type 2 diabetes.
DESIGN AND SETTING
Systematic review and meta-analysis of randomised, controlled trials.
DATA SOURCES
Literature searches were performed across PubMed, EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials from 1966 to May 2016 to identify randomised, controlled trials with more than 1 year follow-up.
OUTCOME MEASURES
Relative risk (RR) with 95% CI was used to evaluate the association between pioglitazone and the risk of major adverse cardiovascular events (MACE: composite of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death) and safety outcomes, after pooling data across trials in a fixed-effects model.
RESULTS
Nine trials with 12 026 participants were enrolled in the current meta-analysis. Pioglitazone therapy was associated with a lower risk of MACE in patients with pre-diabetes or insulin resistance (RR 0.77, 95% CI 0.64 to 0.93), and diabetes (RR 0.83, 95% CI 0.72 to 0.97). Risks of heart failure (RR 1.32; CI 1.14 to 1.54), bone fracture (RR 1.52, 95% CI 1.17 to 1.99), oedema (RR, 1.63; CI 1.52 to 1.75) and weight gain (RR 1.60; CI 1.50 to 1.72) increased in pioglitazone group.
CONCLUSIONS
Pioglitazone was associated with reduced risk of MACE in people with insulin resistance, pre-diabetes and diabetes mellitus. However, the risks of heart failure, bone fracture, oedema and weight gain were increased.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Edema; Fractures, Bone; Humans; Hypoglycemic Agents; Insulin Resistance; Pioglitazone; Prediabetic State; Protective Factors; Randomized Controlled Trials as Topic; Thiazolidinediones; Weight Gain
PubMed: 28057658
DOI: 10.1136/bmjopen-2016-013927 -
The Cochrane Database of Systematic... Sep 2016It is unclear whether people with type 2 diabetes mellitus on insulin monotherapy who do not achieve adequate glycaemic control should continue insulin as monotherapy or... (Review)
Review
Insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control.
BACKGROUND
It is unclear whether people with type 2 diabetes mellitus on insulin monotherapy who do not achieve adequate glycaemic control should continue insulin as monotherapy or can benefit from adding oral glucose-lowering agents to the insulin therapy.
OBJECTIVES
To assess the effects of insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin monotherapy for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and reference lists of articles. The date of the last search was November 2015 for all databases.
SELECTION CRITERIA
Randomised controlled clinical trials of at least two months' duration comparing insulin monotherapy with combinations of insulin with one or more oral glucose-lowering agent in people with type 2 diabetes.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated overall quality of the evidence using GRADE. We summarised data statistically if they were available, sufficiently similar and of sufficient quality. We performed statistical analyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions.
MAIN RESULTS
We included 37 trials with 40 treatment comparisons involving 3227 participants. The duration of the interventions ranged from 2 to 12 months for parallel trials and two to four months for cross-over trials.The majority of trials had an unclear risk of bias in several risk of bias domains. Fourteen trials showed a high risk of bias, mainly for performance and detection bias. Insulin monotherapy, including once-daily long-acting, once-daily intermediate-acting, twice-daily premixed insulin, and basal-bolus regimens (multiple injections), was compared to insulin in combination with sulphonylureas (17 comparisons: glibenclamide = 11, glipizide = 2, tolazamide = 2, gliclazide = 1, glimepiride = 1), metformin (11 comparisons), pioglitazone (four comparisons), alpha-glucosidase inhibitors (four comparisons: acarbose = 3, miglitol = 1), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) (three comparisons: vildagliptin = 1, sitagliptin = 1, saxagliptin = 1) and the combination of metformin and glimepiride (one comparison). No trials assessed all-cause mortality, diabetes-related morbidity or health-related quality of life. Only one trial assessed patients' treatment satisfaction and showed no substantial differences between the addition of either glimepiride or metformin and glimepiride to insulin compared with insulin monotherapy.Insulin-sulphonylurea combination therapy (CT) compared with insulin monotherapy (IM) showed a MD in glycosylated haemoglobin A1c (HbA1c) of -1% (95% confidence interval (CI) -1.6 to -0.5); P < 0.01; 316 participants; 9 trials; low-quality evidence. Insulin-metformin CT compared with IM showed a MD in HbA1c of -0.9% (95% CI -1.2 to -0.5); P < 0.01; 698 participants; 9 trials; low-quality evidence. We could not pool the results of adding pioglitazone to insulin. Insulin combined with alpha-glucosidase inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.2); P < 0.01; 448 participants; 3 trials; low-quality evidence). Insulin combined with DPP-4 inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.4); P < 0.01; 265 participants; 2 trials; low quality evidence. In most trials the participants with CT needed less insulin, whereas insulin requirements increased or remained stable in participants with IM.We did not perform a meta-analysis for hypoglycaemic events because the included studies used different definitions.. In most trials the insulin-sulphonylurea combination resulted in a higher number of mild episodes of hypoglycaemia, compared to the IM group (range: 2.2 to 6.1 episodes per participant in CT versus 2.0 to 2.6 episodes per participant in IM; low-quality evidence). Pioglitazone CT also resulted in more mild to moderate hypoglycaemic episodes compared with IM (range 15 to 90 episodes versus 9 to 75 episodes, respectively; low-quality evidence. The trials that reported hypoglycaemic episodes in the other combinations found comparable numbers of mild to moderate hypoglycaemic events (low-quality evidence).The addition of sulphonylureas resulted in an additional weight gain of 0.4 kg to 1.9 kg versus -0.8 kg to 2.1 kg in the IM group (220 participants; 7 trials; low-quality evidence). Pioglitazone CT caused more weight gain compared to IM: MD 3.8 kg (95% CI 3.0 to 4.6); P < 0.01; 288 participants; 2 trials; low-quality evidence. Metformin CT was associated with weight loss: MD -2.1 kg (95% CI -3.2 to -1.1), P < 0.01; 615 participants; 7 trials; low-quality evidence). DPP-4 inhibitors CT showed weight gain of -0.7 to 1.3 kg versus 0.6 to 1.1 kg in the IM group (362 participants; 2 trials; low-quality evidence). Alpha-glucosidase CT compared to IM showed a MD of -0.5 kg (95% CI -1.2 to 0.3); P = 0.26; 241 participants; 2 trials; low-quality evidence.Users of metformin CT (range 7% to 67% versus 5% to 16%), and alpha-glucosidase inhibitors CT (14% to 75% versus 4% to 35%) experienced more gastro-intestinal adverse effects compared to participants on IM. Two trials reported a higher frequency of oedema with the use of pioglitazone CT (range: 16% to 18% versus 4% to 7% IM).
AUTHORS' CONCLUSIONS
The addition of all oral glucose-lowering agents in people with type 2 diabetes and inadequate glycaemic control who are on insulin therapy has positive effects on glycaemic control and insulin requirements. The addition of sulphonylureas results in more hypoglycaemic events. Additional weight gain can only be avoided by adding metformin to insulin. Other well-known adverse effects of oral glucose-lowering agents have to be taken into account when prescribing oral glucose-lowering agents in addition to insulin therapy.
PubMed: 27640062
DOI: 10.1002/14651858.CD006992.pub2 -
The Cochrane Database of Systematic... Aug 2016Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012.
OBJECTIVES
To assess the effects of pharmacological treatments for Friedreich ataxia.
SEARCH METHODS
On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies.
SELECTION CRITERIA
We considered randomised controlled trials (RCTs) or quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months.
DATA COLLECTION AND ANALYSIS
Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion.In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence).The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low.There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis.
AUTHORS' CONCLUSIONS
Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.
Topics: Antioxidants; Friedreich Ataxia; Heart; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Rare Diseases; Ubiquinone; Ultrasonography; Vitamin E
PubMed: 27572719
DOI: 10.1002/14651858.CD007791.pub4 -
The Journal of Clinical Endocrinology... Feb 2015Various drugs affect body weight as a side effect. (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Various drugs affect body weight as a side effect.
OBJECTIVE
We conducted this systematic review and meta-analysis to summarize the evidence about commonly prescribed drugs and their association with weight change.
DATA SOURCES
MEDLINE, DARE, and the Cochrane Database of Systematic Reviews were searched to identify published systematic reviews as a source for trials.
STUDY SELECTION
We included randomized trials that compared an a priori selected list of drugs to placebo and measured weight change.
DATA EXTRACTION
We extracted data in duplicate and assessed the methodological quality using the Cochrane risk of bias tool.
RESULTS
We included 257 randomized trials (54 different drugs; 84 696 patients enrolled). Weight gain was associated with the use of amitriptyline (1.8 kg), mirtazapine (1.5 kg), olanzapine (2.4 kg), quetiapine (1.1 kg), risperidone (0.8 kg), gabapentin (2.2 kg), tolbutamide (2.8 kg), pioglitazone (2.6 kg), glimepiride (2.1 kg), gliclazide (1.8 kg), glyburide (2.6 kg), glipizide (2.2 kg), sitagliptin (0.55 kg), and nateglinide (0.3 kg). Weight loss was associated with the use of metformin (1.1 kg), acarbose (0.4 kg), miglitol (0.7 kg), pramlintide (2.3 kg), liraglutide (1.7 kg), exenatide (1.2 kg), zonisamide (7.7 kg), topiramate (3.8 kg), bupropion (1.3 kg), and fluoxetine (1.3 kg). For many other remaining drugs (including antihypertensives and antihistamines), the weight change was either statistically nonsignificant or supported by very low-quality evidence.
CONCLUSIONS
Several drugs are associated with weight change of varying magnitude. Data are provided to guide the choice of drug when several options exist and institute preemptive weight loss strategies when obesogenic drugs are prescribed.
Topics: Antipsychotic Agents; Body Weight; Humans; Hypoglycemic Agents; Weight Gain; Weight Loss
PubMed: 25590213
DOI: 10.1210/jc.2014-3421 -
BMC Cardiovascular Disorders Sep 2014Patients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs.
METHODS
We systematically identified and reviewed cohort and case-control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison.
RESULTS
The summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis.
CONCLUSIONS
Use of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.
Topics: Bias; Biomarkers; Blood Glucose; Chi-Square Distribution; Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypoglycemic Agents; Metformin; Odds Ratio; Risk Assessment; Risk Factors; Sulfonylurea Compounds; Thiazolidinediones
PubMed: 25260374
DOI: 10.1186/1471-2261-14-129 -
British Journal of Clinical Pharmacology Aug 2014To determine whether thiazolidinedione use is associated with a risk of bladder cancer. (Meta-Analysis)
Meta-Analysis
AIMS
To determine whether thiazolidinedione use is associated with a risk of bladder cancer.
METHODS
We searched MEDLINE and EMBASE in June 2012 (with PubMed update to July 2013) and conducted meta-analysis on the overall risks of bladder cancer with pioglitazone or rosiglitazone and the risk with different categories of cumulative dose or duration of drug use.
RESULTS
We screened 230 citations and included 18 studies, comprising five randomized controlled trials (RCTs) and 13 observational studies. Meta-analysis showed a significantly higher overall risk of bladder cancer with pioglitazone in RCTs [7878 participants; odds ratio (OR) 2.51, 95% confidence interval (CI) 1.09-5.80] and observational studies (>2.6 million patients; OR for 'ever' users vs. non-users 1.21, 95% CI 1.09-1.35). Subgroup analysis of observational studies by cumulative dose showed the risk of bladder cancer to be greatest with >28.0 g of pioglitazone (OR 1.64, 95% CI 1.28-2.12). A significantly increased risk was found with both 12-24 months (OR 1.41, 95% CI 1.16-1.71) and >24 months (OR 1.51, 95% CI 1.26-1.81) cumulative durations of pioglitazone exposure. No significant risk was seen with rosiglitazone in RCTs (OR 0.84, 95% CI 0.35-2.04) or 'ever' users vs. non-users in observational studies (OR 1.03, 95% CI 0.94-1.12); the evidence for any relationship between bladder cancer risk and rosiglitazone cumulative duration is limited and inconsistent. Direct comparison of pioglitazone to rosiglitazone 'ever' users yielded an OR of 1.25 (95% CI 0.91-1.72).
CONCLUSIONS
A modest but clinically significant increase in the risk of bladder cancer with pioglitazone was found, which appears to be related to cumulative dose and duration of exposure. We recommend that prescribers limit pioglitazone use to shorter durations.
Topics: Data Interpretation, Statistical; Dose-Response Relationship, Drug; Humans; Risk; Thiazolidinediones; Urinary Bladder Neoplasms
PubMed: 24325197
DOI: 10.1111/bcp.12306