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Frontiers in Endocrinology 2023A systematic review and meta-analysis was conducted to synthesize the available data from clinical trials and assess the safety issues of tirzepatide (pancreatitis and... (Meta-Analysis)
Meta-Analysis
PURPOSE
A systematic review and meta-analysis was conducted to synthesize the available data from clinical trials and assess the safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes (T2D) and obesity.
METHODS
A systematic search was conducted in three electronic databases, namely Embase, PubMed, and the Cochrane Library, up until March 1, 2023, to identify randomized controlled trials (RCTs) comparing tirzepatide to either placebo or active hypoglycemic drugs in individuals with T2D and obesity. Heterogeneity was assessed using the I2 value and Cochran's Q test, and a fixed effects model was employed to estimate the safety profile of tirzepatide. The safety outcomes of interest, including pancreatitis, the composite of gallbladder or biliary diseases, cholecystitis, and cholelithiasis and biliary diseases, were evaluated. (The composite of gallbladder or biliary diseases incorporated cholelithiasis, cholecystitis, other gallbladder disorders, and biliary diseases.).
RESULTS
A total of nine trials with 9871 participants (6828 in the tirzepatide group and 3043 in the control group) that met the pre-specified criteria were included. When compared to all control groups consisting of basal insulin (glargine or degludec), selective GLP1-RA (dulaglutide or semaglutide once weekly), and placebo, an increased risk of pancreatitis was not found to be significantly associated with tirzepatide (RR 1.46, [95% CI] 0.59 to 3.61; I2 = 0.0%, p = 0.436). For gallbladder or biliary disease, the composite of gallbladder or biliary disease was significantly associated with tirzepatide compared with placebo or basal insulin (RR 1.97, [95% CI] 1.14 to 3.42; I2 = 0.0%, p = 0.558), but not with the risk of cholelithiasis, cholecystitis or biliary diseases.
CONCLUSION
Based on the currently available data, tirzepatide appears to be safe regarding the risk of pancreatitis. However, the increased risk of the composite outcome of gallbladder or biliary diseases observed in RCTs warrants further attention from physicians in clinical practice.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023412400.
Topics: Humans; Cholecystitis; Diabetes Mellitus, Type 2; Insulin Glargine; Obesity; Pancreatitis; Cholelithiasis
PubMed: 37908750
DOI: 10.3389/fendo.2023.1214334 -
Clinical Toxicology (Philadelphia, Pa.) Nov 2014Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. (Review)
Review
CONTEXT
Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion.
OBJECTIVE
To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations.
METHODS
Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types.
RESULTS
The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5-2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue.
CONCLUSIONS
The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.
Topics: Animals; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Overdose; Guidelines as Topic; Hospitalization; Humans; Insulin; Length of Stay; Observational Studies as Topic; Treatment Outcome; Vasoconstrictor Agents
PubMed: 25283255
DOI: 10.3109/15563650.2014.965827 -
PloS One 2023Tirzeptide is a novel glucagon-like peptide-1 receptor (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) drug, which shows good efficiency for weight loss.... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Tirzeptide is a novel glucagon-like peptide-1 receptor (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) drug, which shows good efficiency for weight loss. Therefore, we aim to investigate the efficacy and safety of tirzepatide for weight loss in type 2 diabetes mellitus (T2DM) and obesity patients in this meta-analysis study.
METHODS
Cochrane Library, PubMed, Embase, Clinical Trials, and Web of Science were searched from inception to October 5, 2022. All randomized controlled trials (RCTs) were included. The odds ratio (OR) was calculated using fixed-effects or random-effects models by Review Manager 5.3 software.
RESULTS
In total, ten studies (12 reports) involving 9,873 patients were identified. A significant loss body weight in the tirzepatide group versus the placebo by -9.81 kg (95% CI (-12.09, -7.52), GLP-1 RAs by -1.05 kg (95% CI (-1.48, -0.63), and insulin by -1.93 kg (95% CI (-2.81, -1.05), respectively. In sub-analysis, the body weight of patients was significantly reduced in three tirzepatide doses (5 mg, 10 mg, and 15 mg) when compared with those of the placebo/GLP-1 RA/insulin. In terms of safety, the incidence of any adverse events and adverse events leading to study drug discontinuation was higher in the tirzepatide group, but the incidence of serious adverse events and hypoglycaemia was lower. Additionally, the gastrointestinal adverse events (including diarrhea, nausea, vomiting and decreased appetite) of tirzepatide were higher than those of placebo/basal insulin, but similar to GLP-1 RAs.
CONCLUSION
In conclusion, tirzeptide can significantly reduce the weight of T2DM and patient with obesity, and it is a potential therapeutic regimen for weight-loss, but we need to be vigilant about its gastrointestinal reaction.
Topics: Humans; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Insulin; Weight Loss; Obesity; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor
PubMed: 37141329
DOI: 10.1371/journal.pone.0285197 -
PLoS Medicine Aug 2019Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However,... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown.
METHODS AND FINDINGS
PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies (n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies (n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference -107.7 g, 95% CI -182.3 to -32.7, I2 = 83%, p = 0.005) and lower ponderal indices (mean difference -0.13 kg/m3, 95% CI -0.26 to 0.00, I2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies (n = 411 infants) reported measures of infant growth (18-24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I2 = 4%, p = 0.03). Three studies (n = 520 children) reported mid-childhood growth parameters (5-9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, I2 = 7%, p = 0.005) following metformin exposure than following insulin exposure, although the difference in absolute weights between the groups was not significantly different (p = 0.09). Limited evidence (1 study with data treated as 2 cohorts) suggested that adiposity indices (abdominal [p = 0.02] and visceral [p = 0.03] fat volumes) may be higher in children born to metformin-treated compared to insulin-treated mothers. Study limitations include heterogeneity in metformin dosing, heterogeneity in diagnostic criteria for GDM, and the scarcity of reporting of childhood outcomes.
CONCLUSIONS
Following intrauterine exposure to metformin for treatment of maternal GDM, neonates are significantly smaller than neonates whose mothers were treated with insulin during pregnancy. Despite lower average birth weight, metformin-exposed children appear to experience accelerated postnatal growth, resulting in heavier infants and higher BMI by mid-childhood compared to children whose mothers were treated with insulin. Such patterns of low birth weight and postnatal catch-up growth have been reported to be associated with adverse long-term cardio-metabolic outcomes. This suggests a need for further studies examining longitudinal perinatal and childhood outcomes following intrauterine metformin exposure. This review protocol was registered with PROSPERO under registration number CRD42018117503.
Topics: Child Development; Child, Preschool; Diabetes, Gestational; Female; Humans; Hypoglycemic Agents; Infant; Infant, Newborn; Insulin; Metformin; Pregnancy
PubMed: 31386659
DOI: 10.1371/journal.pmed.1002848 -
BMJ Open Aug 2017To summarise incidence and prevalence of diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D) for the overall patient population and different subgroups... (Review)
Review
OBJECTIVES
To summarise incidence and prevalence of diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D) for the overall patient population and different subgroups (age, sex, geographical region, ethnicity and type of insulin administration).
DESIGN
Systematic literature review (SLR).
DATA SOURCES
Medline (via PubMed) and Embase (1 January 2000 to 23 June 2016).
STUDY SELECTION
Peer-reviewed observational studies with reported data on the incidence or prevalence of DKA in T1D adults were included. A single reviewer completed the study screening and selection process and a second reviewer performed an additional screening of approximately 20% of the publications; two reviewers independently conducted the quality assessment; the results were narratively synthesised.
RESULTS
Out of 1082 articles, 19 met the inclusion and exclusion criteria, with two additional studies identified that did not specify the patient age range and are therefore not included in the SLR. Overall, eight studies reported incidence with a range of 0-56 per 1000 person-years (PYs), with one outlying study reporting an incidence of 263 per 1000 PYs. Eleven studies reported prevalence with a range of 0-128 per 1000 people. Prevalence of DKA decreased with increasing age. Subgroup analyses were performed using data from no more than two studies per subgroup. There was a higher prevalence of DKA reported in women, non-whites and patients treated with insulin injections compared with men, whites and patients using continuous subcutaneous insulin infusion pumps, respectively.
CONCLUSIONS
To our knowledge, this is the first SLR on the epidemiology of DKA in T1D adults. Despite an increasing prevalence of T1D in recent years, DKA in adults has been poorly characterised. In an era when the benefit-risk profiles of new antidiabetic therapies are being evaluated, including the potential risk of DKA, there is a clear need to better elucidate the expected rate of DKA among T1D adults.
Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Hypoglycemic Agents; Infusion Pumps; Injections; Insulin; Male
PubMed: 28765134
DOI: 10.1136/bmjopen-2017-016587 -
Human Reproduction (Oxford, England) Jun 2023What is the influence of body composition during childhood, adolescence, and adulthood, as well as metabolic parameters, on incident polycystic ovary syndrome (PCOS)? (Meta-Analysis)
Meta-Analysis
STUDY QUESTION
What is the influence of body composition during childhood, adolescence, and adulthood, as well as metabolic parameters, on incident polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER
Excess body fat, even during childhood/adolescence, and metabolic parameters, suggestive of hyperinsulinaemia/insulin resistance, significantly impact the risk of PCOS in a linear fashion.
WHAT IS KNOWN ALREADY
Observational and Mendelian randomization (MR) data have demonstrated an association between adulthood overweight/obesity and development of PCOS. However, the contribution of body composition in childhood/adolescence to incident PCOS is unclear, as is the influence of childhood overweight/obesity.
STUDY DESIGN, SIZE, DURATION
We conducted a systematic review and meta-analysis and integrated our results with a previously published systematic review. Two blinded investigators screened abstracts published between November 2010 and May 2021. Furthermore, we incorporated summary statistics from genome-wide association study (GWAS) data in subjects of European ancestry. Adult overweight was defined as BMI ≥ 25 kg/m2 and obesity as BMI ≥ 30 kg/m2; in Asian subjects, overweight was defined as BMI ≥ 23 kg/m2 and obesity as BMI ≥ 25 kg/m2.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We utilized meta-analysis and MR together to allow synthesis of genetic and observational data. For the systematic review, the search revealed 71 studies, of which 63 were included in meta-analysis by calculating odds ratios (ORs) using the random-effects model. Furthermore, we conducted a two-sample MR study of GWAS data to determine the impact of childhood and adult body size (defined categorically by BMI and childhood body size proportions), abnormal body composition and metabolic parameters (higher fasting serum insulin or lower sex hormone-binding globulin (SHBG) concentration) on the odds of incident PCOS via the inverse-variance weighted method.
MAIN RESULTS AND THE ROLE OF CHANCE
Significant associations were shown between body composition and PCOS incidence. From the systematic review/meta-analysis, women with overweight (OR 3.80, 2.87-5.03), obesity (OR 4.99, 3.74-6.67), and central obesity (OR 2.93, 2.08-4.12) had increased odds of PCOS. For adolescents with overweight and/or obesity, the PCOS odds were greater than for adults. From MR, for every standard deviation increase in BMI (4.8 kg/m2), the odds of PCOS increased by 2.76 (2.27-3.35). Childhood body size had an independent effect on PCOS odds after adjusting for adult body size (OR: 2.56, 1.57-4.20). Genetically determined body fat percentage (OR 3.05, 2.24-4.15), whole body fat mass (OR 2.53, 2.04-3.14), fasting serum insulin (OR 6.98, 2.02-24.13), and SHBG concentration (OR 0.74, 0.64-0.87) were all significantly associated with PCOS in a linear relation.
LIMITATIONS, REASONS FOR CAUTION
The meta-analysis included studies which were cross-sectional and retrospective, limiting our ability to determine causality. MR was limited by interrogating subjects only of European ancestry and including cases classified by either self-diagnosis or diagnostic criteria.
WIDER IMPLICATIONS OF THE FINDINGS
Our study demonstrates for the first time a critical role of the impact of excess childhood/adolescent adiposity on the pathophysiology of adult PCOS. Our results, driven by genetically determined childhood/adolescent body composition, higher BMI, hyperinsulinaemia, and lower SHBG, clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype. Overall, effective weight maintenance, even from the early years, is likely to reduce the risk of this reproductive endocrine disorder.
STUDY FUNDING/COMPETING INTEREST(S)
S.S.Z. was funded by a National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship. U.A. is chair of the NIHR Steering Committee Trial-CASSANDRA-DN. No other authors declare any sources of funding or relevant conflicts of interest. The authors declare that the research was conducted in the absence of any commercial or financial relations that could be construed as a potential conflict of interest.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Humans; Female; Polycystic Ovary Syndrome; Overweight; Adiposity; Retrospective Studies; Genome-Wide Association Study; Mendelian Randomization Analysis; Body Mass Index; Obesity; Insulin Resistance; Insulins
PubMed: 37015099
DOI: 10.1093/humrep/dead053 -
Acta Diabetologica May 2023To expand the evidence base for the clinical use of metformin, we conducted a meta-analysis of randomized controlled trials (RCTs) comparing the efficacy and safety of... (Meta-Analysis)
Meta-Analysis Review
Short-term neonatal outcomes in women with gestational diabetes treated using metformin versus insulin: a systematic review and meta-analysis of randomized controlled trials.
AIMS
To expand the evidence base for the clinical use of metformin, we conducted a meta-analysis of randomized controlled trials (RCTs) comparing the efficacy and safety of metformin versus insulin with respect to short-term neonatal outcomes.
METHODS
A comprehensive search of electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) was performed. Two reviewers extracted the data and calculated pooled estimates by use of a random-effects model. In total, 24 studies involving 4355 participants met the eligibility criteria and were included in the quantitative analyses.
RESULTS
Unlike insulin, metformin lowered neonatal birth weights (mean difference - 122.76 g; 95% confidence interval [CI] - 178.31, - 67.21; p < 0.0001), the risk of macrosomia (risk ratio [RR] 0.68; 95% CI 0.54, 0.86; p = 0.001), the incidence of neonatal intensive care unit admission (RR 0.73; 95% CI 0.61, 0.88; p = 0.0009), and the incidence of neonatal hypoglycemia (RR 0.65; 95% CI 0.52, 0.81; p = 0.0001). Subgroup analysis based on the maximum daily oral dose of metformin indicated that metformin-induced neonatal birth weight loss was independent of the oral dose.
CONCLUSIONS
Our meta-analysis provides further evidence that metformin is a safe oral antihyperglycemic drug and has some benefits over insulin when used for the treatment of gestational diabetes, without an increased risk of short-term neonatal adverse outcomes. Metformin may be particularly useful in women with gestational diabetes at high risk for neonatal hypoglycemia, women who want to limit maternal and fetal weight gain, and women with an inability to afford or use insulin safely.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Diabetes, Gestational; Metformin; Insulin; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Hypoglycemia; Birth Weight; Weight Gain
PubMed: 36593391
DOI: 10.1007/s00592-022-02016-5 -
Journal of Gastrointestinal and Liver... Mar 2021Vasoactive agents with endoscopic therapy are used to treat acute variceal bleeding (AVB). There are two main groups of vasoactive agents: terlipressin and vasopressin... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Vasoactive agents with endoscopic therapy are used to treat acute variceal bleeding (AVB). There are two main groups of vasoactive agents: terlipressin and vasopressin (T-V), and octreotide and somatostatin (O-S). However, the benefit/harm balance is unclear. Our aim was to assess the efficacy and safety of T-V versus O-S for the management of AVB.
METHODS
We performed a systematic search for randomized controlled trials (RCTs) in PubMed, Scopus, and CENTRAL. Our main outcomes were mortality and adverse events. Secondary outcomes were bleeding control, rebleeding, blood transfusion, hospital stay. We evaluated the certainty of evidence using GRADE methodology.
RESULTS
We included 21 RCTs. The risk of mortality (RR: 1.01; 95%CI: 0.83-1.22), bleeding control (RR: 0.96; 95%CI: 0.91-1.02; I 2 =53%), early rebleeding (RR: 0.91; 95%CI: 0.66-1.24: I 2 =0%), late rebleeding (RR: 0.94; 95 CI: 0.56-1.60; I 2 =0%), blood transfusion (MD: 0.04; 95%CI: -0.31-0.39; I 2 =68%) and hospital stay (MD: -1.06; 95%CI: -2.80-0.69; I 2 =0%) were similar between T-V and O-S groups. Only 15 studies reported adverse events, which were significantly higher in the T-V compared to the O-S group (RR 2.39; 95%CI: 1.58-3.63; I 2 =57%). The certainty of evidence was moderate for the main outcomes, and low or very low for others.
CONCLUSIONS
In cirrhotic patients with AVB, those treated with T-V had similar mortality risk compared to O-S. However, the use of T-V showed an increased risk of adverse events compared to O-S.
Topics: Adult; Aged; Blood Transfusion; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Length of Stay; Liver Cirrhosis; Male; Middle Aged; Octreotide; Recurrence; Somatostatin; Terlipressin; Treatment Outcome; Vasopressins
PubMed: 33723542
DOI: 10.15403/jgld-3191 -
Treatments for women with gestational diabetes mellitus: an overview of Cochrane systematic reviews.The Cochrane Database of Systematic... Aug 2018Successful treatments for gestational diabetes mellitus (GDM) have the potential to improve health outcomes for women with GDM and their babies. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Successful treatments for gestational diabetes mellitus (GDM) have the potential to improve health outcomes for women with GDM and their babies.
OBJECTIVES
To provide a comprehensive synthesis of evidence from Cochrane systematic reviews of the benefits and harms associated with interventions for treating GDM on women and their babies.
METHODS
We searched the Cochrane Database of Systematic Reviews (5 January 2018) for reviews of treatment/management for women with GDM. Reviews of pregnant women with pre-existing diabetes were excluded.Two overview authors independently assessed reviews for inclusion, quality (AMSTAR; ROBIS), quality of evidence (GRADE), and extracted data.
MAIN RESULTS
We included 14 reviews. Of these, 10 provided relevant high-quality and low-risk of bias data (AMSTAR and ROBIS) from 128 randomised controlled trials (RCTs), 27 comparisons, 17,984 women, 16,305 babies, and 1441 children. Evidence ranged from high- to very low-quality (GRADE). Only one effective intervention was found for treating women with GDM.EffectiveLifestyle versus usual careLifestyle intervention versus usual care probably reduces large-for-gestational age (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.50 to 0.71; 6 RCTs, N = 2994; GRADE moderate-quality).PromisingNo evidence for any outcome for any comparison could be classified to this category.Ineffective or possibly harmful Lifestyle versus usual careLifestyle intervention versus usual care probably increases the risk of induction of labour (IOL) suggesting possible harm (average RR 1.20, 95% CI 0.99 to 1.46; 4 RCTs, N = 2699; GRADE moderate-quality).Exercise versus controlExercise intervention versus control for return to pre-pregnancy weight suggested ineffectiveness (body mass index, BMI) MD 0.11 kg/m², 95% CI -1.04 to 1.26; 3 RCTs, N = 254; GRADE moderate-quality).Insulin versus oral therapyInsulin intervention versus oral therapy probably increases the risk of IOL suggesting possible harm (RR 1.3, 95% CI 0.96 to 1.75; 3 RCTs, N = 348; GRADE moderate-quality).Probably ineffective or harmful interventionsInsulin versus oral therapyFor insulin compared to oral therapy there is probably an increased risk of the hypertensive disorders of pregnancy (RR 1.89, 95% CI 1.14 to 3.12; 4 RCTs, N = 1214; GRADE moderate-quality).InconclusiveLifestyle versus usual careThe evidence for childhood adiposity kg/m² (RR 0.91, 95% CI 0.75 to 1.11; 3 RCTs, N = 767; GRADE moderate-quality) and hypoglycaemia was inconclusive (average RR 0.99, 95% CI 0.65 to 1.52; 6 RCTs, N = 3000; GRADE moderate-quality).Exercise versus controlThe evidence for caesarean section (RR 0.86, 95% CI 0.63 to 1.16; 5 RCTs, N = 316; GRADE moderate quality) and perinatal death or serious morbidity composite was inconclusive (RR 0.56, 95% CI 0.12 to 2.61; 2 RCTs, N = 169; GRADE moderate-quality).Insulin versus oral therapyThe evidence for the following outcomes was inconclusive: pre-eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 RCTs, N = 2060), caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 RCTs, N = 1988), large-for-gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 RCTs, N = 2352), and perinatal death or serious morbidity composite (RR 1.03; 95% CI 0.84 to 1.26; 2 RCTs, N = 760). GRADE assessment was moderate-quality for these outcomes.Insulin versus dietThe evidence for perinatal mortality was inconclusive (RR 0.74, 95% CI 0.41 to 1.33; 4 RCTs, N = 1137; GRADE moderate-quality).Insulin versus insulinThe evidence for insulin aspart versus lispro for risk of caesarean section was inconclusive (RR 1.00, 95% CI 0.91 to 1.09; 3 RCTs, N = 410; GRADE moderate quality).No conclusions possibleNo conclusions were possible for: lifestyle versus usual care (perineal trauma, postnatal depression, neonatal adiposity, number of antenatal visits/admissions); diet versus control (pre-eclampsia, caesarean section); myo-inositol versus placebo (hypoglycaemia); metformin versus glibenclamide (hypertensive disorders of pregnancy, pregnancy-induced hypertension, death or serious morbidity composite, insulin versus oral therapy (development of type 2 diabetes); intensive management versus routine care (IOL, large-for-gestational age); post- versus pre-prandial glucose monitoring (large-for-gestational age). The evidence ranged from moderate-, low- and very low-quality.
AUTHORS' CONCLUSIONS
Currently there is insufficient high-quality evidence about the effects on health outcomes of relevance for women with GDM and their babies for many of the comparisons in this overview comparing treatment interventions for women with GDM. Lifestyle changes (including as a minimum healthy eating, physical activity and self-monitoring of blood sugar levels) was the only intervention that showed possible health improvements for women and their babies. Lifestyle interventions may result in fewer babies being large. Conversely, in terms of harms, lifestyle interventions may also increase the number of inductions. Taking insulin was also associated with an increase in hypertensive disorders, when compared to oral therapy. There was very limited information on long-term health and health services costs. Further high-quality research is needed.
Topics: Diabetes, Gestational; Exercise; Female; Humans; Hypertension; Hypoglycemic Agents; Infant, Newborn; Insulin; Labor, Induced; Life Style; Pregnancy; Pregnancy Complications, Cardiovascular; Randomized Controlled Trials as Topic; Review Literature as Topic
PubMed: 30103263
DOI: 10.1002/14651858.CD012327.pub2 -
The Cochrane Database of Systematic... Sep 2018Diabetes is the commonest cause of chronic kidney disease (CKD). Both conditions commonly co-exist. Glucometabolic changes and concurrent dialysis in diabetes and CKD... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Diabetes is the commonest cause of chronic kidney disease (CKD). Both conditions commonly co-exist. Glucometabolic changes and concurrent dialysis in diabetes and CKD make glucose-lowering challenging, increasing the risk of hypoglycaemia. Glucose-lowering agents have been mainly studied in people with near-normal kidney function. It is important to characterise existing knowledge of glucose-lowering agents in CKD to guide treatment.
OBJECTIVES
To examine the efficacy and safety of insulin and other pharmacological interventions for lowering glucose levels in people with diabetes and CKD.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
All randomised controlled trials (RCTs) and quasi-RCTs looking at head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in people with diabetes and CKD (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m) were eligible.
DATA COLLECTION AND ANALYSIS
Four authors independently assessed study eligibility, risk of bias, and quality of data and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD). 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
Forty-four studies (128 records, 13,036 participants) were included. Nine studies compared sodium glucose co-transporter-2 (SGLT2) inhibitors to placebo; 13 studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; 2 studies compared glucagon-like peptide-1 (GLP-1) agonists to placebo; 8 studies compared glitazones to no glitazone treatment; 1 study compared glinide to no glinide treatment; and 4 studies compared different types, doses or modes of administration of insulin. In addition, 2 studies compared sitagliptin to glipizide; and 1 study compared each of sitagliptin to insulin, glitazars to pioglitazone, vildagliptin to sitagliptin, linagliptin to voglibose, and albiglutide to sitagliptin. Most studies had a high risk of bias due to funding and attrition bias, and an unclear risk of detection bias.Compared to placebo, SGLT2 inhibitors probably reduce HbA1c (7 studies, 1092 participants: MD -0.29%, -0.38 to -0.19 (-3.2 mmol/mol, -4.2 to -2.2); I = 0%), fasting blood glucose (FBG) (5 studies, 855 participants: MD -0.48 mmol/L, -0.78 to -0.19; I = 0%), systolic blood pressure (BP) (7 studies, 1198 participants: MD -4.68 mmHg, -6.69 to -2.68; I = 40%), diastolic BP (6 studies, 1142 participants: MD -1.72 mmHg, -2.77 to -0.66; I = 0%), heart failure (3 studies, 2519 participants: RR 0.59, 0.41 to 0.87; I = 0%), and hyperkalaemia (4 studies, 2788 participants: RR 0.58, 0.42 to 0.81; I = 0%); but probably increase genital infections (7 studies, 3086 participants: RR 2.50, 1.52 to 4.11; I = 0%), and creatinine (4 studies, 848 participants: MD 3.82 μmol/L, 1.45 to 6.19; I = 16%) (all effects of moderate certainty evidence). SGLT2 inhibitors may reduce weight (5 studies, 1029 participants: MD -1.41 kg, -1.8 to -1.02; I = 28%) and albuminuria (MD -8.14 mg/mmol creatinine, -14.51 to -1.77; I = 11%; low certainty evidence). SGLT2 inhibitors may have little or no effect on the risk of cardiovascular death, hypoglycaemia, acute kidney injury (AKI), and urinary tract infection (low certainty evidence). It is uncertain whether SGLT2 inhibitors have any effect on death, end-stage kidney disease (ESKD), hypovolaemia, fractures, diabetic ketoacidosis, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, DPP-4 inhibitors may reduce HbA1c (7 studies, 867 participants: MD -0.62%, -0.85 to -0.39 (-6.8 mmol/mol, -9.3 to -4.3); I = 59%) but may have little or no effect on FBG (low certainty evidence). DPP-4 inhibitors probably have little or no effect on cardiovascular death (2 studies, 5897 participants: RR 0.93, 0.77 to 1.11; I = 0%) and weight (2 studies, 210 participants: MD 0.16 kg, -0.58 to 0.90; I = 29%; moderate certainty evidence). Compared to placebo, DPP-4 inhibitors may have little or no effect on heart failure, upper respiratory tract infections, and liver impairment (low certainty evidence). Compared to placebo, it is uncertain whether DPP-4 inhibitors have any effect on eGFR, hypoglycaemia, pancreatitis, pancreatic cancer, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, GLP-1 agonists probably reduce HbA1c (7 studies, 867 participants: MD -0.53%, -1.01 to -0.06 (-5.8 mmol/mol, -11.0 to -0.7); I = 41%; moderate certainty evidence) and may reduce weight (low certainty evidence). GLP-1 agonists may have little or no effect on eGFR, hypoglycaemia, or discontinuation due to adverse effects (low certainty evidence). It is uncertain whether GLP-1 agonists reduce FBG, increase gastrointestinal symptoms, or affect the risk of pancreatitis (very low certainty evidence).Compared to placebo, it is uncertain whether glitazones have any effect on HbA1c, FBG, death, weight, and risk of hypoglycaemia (very low certainty evidence).Compared to glipizide, sitagliptin probably reduces hypoglycaemia (2 studies, 551 participants: RR 0.40, 0.23 to 0.69; I = 0%; moderate certainty evidence). Compared to glipizide, sitagliptin may have had little or no effect on HbA1c, FBG, weight, and eGFR (low certainty evidence). Compared to glipizide, it is uncertain if sitagliptin has any effect on death or discontinuation due to adverse effects (very low certainty).For types, dosages or modes of administration of insulin and other head-to-head comparisons only individual studies were available so no conclusions could be made.
AUTHORS' CONCLUSIONS
Evidence concerning the efficacy and safety of glucose-lowering agents in diabetes and CKD is limited. SGLT2 inhibitors and GLP-1 agonists are probably efficacious for glucose-lowering and DPP-4 inhibitors may be efficacious for glucose-lowering. Additionally, SGLT2 inhibitors probably reduce BP, heart failure, and hyperkalaemia but increase genital infections, and slightly increase creatinine. The safety profile for GLP-1 agonists is uncertain. No further conclusions could be made for the other classes of glucose-lowering agents including insulin. More high quality studies are required to help guide therapeutic choice for glucose-lowering in diabetes and CKD.
Topics: Cause of Death; Diabetes Mellitus; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glipizide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones
PubMed: 30246878
DOI: 10.1002/14651858.CD011798.pub2