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Frontiers in Endocrinology 2023The safety of different sodium-glucose transporter 2 (SGLT-2) inhibitors remains uncertain due to the lack of head-to-head comparisons. (Comparative Study)
Comparative Study Meta-Analysis
Comparative safety of different sodium-glucose transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUNDS
The safety of different sodium-glucose transporter 2 (SGLT-2) inhibitors remains uncertain due to the lack of head-to-head comparisons.
METHODS
This network meta-analysis (NMA) was performed to compare the safety of nine SGLT-2 inhibitors in patients with type 2 diabetes (T2DM). PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for studies published in English before August 30, 2022. Published and unpublished randomized controlled trials (RCTs) comparing the safety of individual SGLT-2 inhibitors in patients with T2DM were included. A Bayesian NMA with random effects model was applied. Subgroup and sensitivity analyses were performed. The quality of the evidence was evaluated using the Confidence in Network Meta-Analysis framework.
RESULTS
Nine SGLT-2 inhibitors were evaluated in 113 RCTs (12 registries) involving 105,293 adult patients. Reproductive tract infections (RTIs) were reported in 1,967 (4.51%) and 276 (1.01%) patients in the SGLT-2 inhibitor and placebo groups, respectively. Furthermore, pollakiuria was reported in 233 (2.66%) and 45 (0.84%) patients, respectively. Compared to placebo, a significantly higher risk of RTIs was observed with canagliflozin, ertugliflozin, empagliflozin, remogliflozin, dapagliflozin, and sotagliflozin, but not with luseogliflozin and ipragliflozin, regardless of gender. An increased risk of pollakiuria was observed with dapagliflozin [odds ratio (OR) 10.40, 95% confidence interval (CI) 1.60-157.94) and empagliflozin (OR 5.81, 95%CI 1.79-32.97). Remogliflozin (OR 6.45, 95%CI 2.18-27.79) and dapagliflozin (OR 1.33, 95%CI 1.10-1.62) were associated with an increased risk of urinary tract infections (UTIs). Instead, the included SGLT-2 inhibitors had a protective effect against acute kidney injury (AKI). No significant differences were found for hypovolemia, renal impairment or failure, fracture, diabetic ketoacidosis (DKA), amputation, and severe hypoglycemia between the SGLT-2 inhibitor and the placebo groups.
CONCLUSION
In patients with T2DM, dapagliflozin was associated with an increased risk of RTIs, pollakiuria, and UTIs. Empagliflozin increased the risk of RTIs and pollakiuria. Remogliflozin increased the risk of UTIs. None of the SGLT-2 inhibitors showed a significant difference from the placebo for hypovolemia, renal impairment or failure, fracture, DKA, amputation, and severe hypoglycemia. The findings guide the selection of SGLT-2 inhibitors for patients with T2DM based on the patient's profiles to maximize safety.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier CRD42022334644.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Fractures, Bone; Hypoglycemia; Hypovolemia; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37701900
DOI: 10.3389/fendo.2023.1238399 -
Acta Cardiologica May 2024The purpose of this systematic review and meta-analysis was to evaluate the common clinical adverse events associated with sodium/glucose cotransporter-2 inhibitor... (Meta-Analysis)
Meta-Analysis Review
The association between sodium/glucose cotransporter-2 inhibitors and adverse clinical events in patients with chronic kidney disease: a systematic review and meta-analysis of randomised controlled trials.
BACKGROUND
The purpose of this systematic review and meta-analysis was to evaluate the common clinical adverse events associated with sodium/glucose cotransporter-2 inhibitor (SGLT2i) use compared to placebo in patients with chronic kidney disease (CKD) with or without type 2 diabetes.
METHODS
Twelve articles were chosen a systematic search of the PubMed, Embase, and Cochrane Library databases. We screened for randomised placebo-controlled trials. The main clinical adverse events included diabetes ketoacidosis (DKA), amputation, and volume depletion. We performed heterogeneity testing and assessment of publication bias.
RESULTS
In all, 65 600 patients were included in the analysis. Compared to placebo, SGLT2i may increase the risk of DKA and volume depletion in patients with CKD with or without type 2 diabetes. For DKA, compared with placebo, the combined effect of SGLT2i was OR 2.03 (95% CI: 1.28 to 3.23 I: 2.3%, P: 0.420). For volume depletion, compared with placebo, the combined effect of SGLT2i was OR 1.24 (95% CI: 1.13 to 1.37 I: 0.0%, P: 0.484). For the risk of amputation, despite low heterogeneity for amputation, the forest plot indicated no statistical significance, and thus it cannot be concluded that SGLT2i increases the risk of amputation. Compared with placebo, the combined effect of SGLT2i was OR 1.10 (95% CI: 0.94 to 1.29 I: 0.0%, P: 0.642).
CONCLUSION
The use of SGLT2i may increase the risk of DKA and volume depletion in patients with chronic renal insufficiency with or without type 2 diabetes.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Renal Insufficiency, Chronic; Randomized Controlled Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis
PubMed: 37642395
DOI: 10.1080/00015385.2023.2250949 -
BMC Endocrine Disorders Aug 2023Autoimmune/type 1 diabetes mellitus (T1DM) is a recently described rare occurrence following the administration of adjuvants such as coronavirus disease 2019 (COVID-19)...
BACKGROUND
Autoimmune/type 1 diabetes mellitus (T1DM) is a recently described rare occurrence following the administration of adjuvants such as coronavirus disease 2019 (COVID-19) vaccines. This systematic review aimed to review all available literature on the potential association between COVID-19 vaccines and T1DM.
METHODS
The Directory of Open Access Journals, MEDLINE, Google Scholar, and Scopus were systematically searched for all published studies from inception to July 2022. Articles reporting T1DM development within 8 weeks of administration of COVID-19 vaccine were included. Two reviewers independently performed the risk of bias assessment following the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports.
RESULTS
Eight eligible studies were retrieved, comprising 12 patients diagnosed with T1DM after being vaccinated with a COVID-19 vaccine. Six patients (50%) reported T1DM after receiving the second dose. Five patients (41.7%) presented with diabetic ketoacidosis, of which four presented within the first eight days after vaccination. Five patients (41.7%) had genetic susceptibility, with RNA binding motif protein 45 (RBM45/DRB1) and major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) mutations being prominent.
INTERPRETATION
In this review, we have shown a small number of new-onset diabetes cases coincidently occurring soon after the COVID-19 vaccine, especially in those with genetic susceptibility. Despite being older, these patients had a similar phenotype to T1DM. While there might be a causal relationship between COVID-19 vaccines and T1DM development, this should not influence decisions regarding vaccination since the overall benefit outweighs the risk. Further larger prospective trials are needed to assess causal relationship and to clarify the potential roles of COVID-19 vaccine-derived antigens in autoimmune disease development.
PROTOCOL REGISTRATION
PROSPERO-CRD42022342093.
Topics: Humans; Diabetes Mellitus, Type 1; COVID-19 Vaccines; Genetic Predisposition to Disease; Prospective Studies; COVID-19; Vaccination; Nerve Tissue Proteins; RNA-Binding Proteins
PubMed: 37542216
DOI: 10.1186/s12902-023-01424-0 -
Turkish Journal of Emergency Medicine 2023The first-line treatment of diabetes ketoacidosis (DKA) involves fluid resuscitation with normal saline infusion to correct hypovolemia. Hyperchloremic metabolic... (Review)
Review
The first-line treatment of diabetes ketoacidosis (DKA) involves fluid resuscitation with normal saline infusion to correct hypovolemia. Hyperchloremic metabolic acidosis from aggressive normal saline administration was associated with worse clinical outcomes in managing DKA. Other choices for normal saline include balanced electrolyte solutions (BESs). This study aimed to compare the clinical effects between BESs and normal saline in managing DKA. This study was a systematic review of probing articles published from inception to October 2021 in Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Google Scholar, and Scopus. Eight randomized controlled trials with a total of 595 individuals were included. The data were analyzed at 95% confidence level using random-effects models. For the primary outcomes, there was no difference in the duration of DKA resolution. (Mean difference [MD] -4.73, 95% confidence interval [CI] -2.72-4.92; = 92%; = 0.180). However, there was a significantly lower postresuscitation chloride concentration in the BES (MD 2.96 95% CI - 4.86 to - 1.06; = 59%; = 0.002). For the secondary outcomes, there was a significant reduction in duration for normalization of bicarbonate in the BES group (MD 3.11 95% CI - 3.98-2.23; = 5%; = 0.0004). There were no significant differences between groups in duration for recovery of pH, intensive unit admission, and adverse events (mortality and acute renal failure). Resuscitation with BES was associated with decreased chloride and increased bicarbonate values in DKA patients. It suggests that BES prevents DKA patients from hyperchloremic metabolic acidosis.
PubMed: 37529790
DOI: 10.4103/tjem.tjem_355_22 -
Frontiers in Pharmacology 2023Sodium-glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However,...
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM. We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388). Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score. https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.
PubMed: 37397500
DOI: 10.3389/fphar.2023.1145587 -
JAMA Network Open Jun 2023There are reports of increasing incidence of pediatric diabetes since the onset of the COVID-19 pandemic. Given the limitations of individual studies that examine this... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
There are reports of increasing incidence of pediatric diabetes since the onset of the COVID-19 pandemic. Given the limitations of individual studies that examine this association, it is important to synthesize estimates of changes in incidence rates.
OBJECTIVE
To compare the incidence rates of pediatric diabetes during and before the COVID-19 pandemic.
DATA SOURCES
In this systematic review and meta-analysis, electronic databases, including Medline, Embase, the Cochrane database, Scopus, and Web of Science, and the gray literature were searched between January 1, 2020, and March 28, 2023, using subject headings and text word terms related to COVID-19, diabetes, and diabetic ketoacidosis (DKA).
STUDY SELECTION
Studies were independently assessed by 2 reviewers and included if they reported differences in incident diabetes cases during vs before the pandemic in youths younger than 19 years, had a minimum observation period of 12 months during and 12 months before the pandemic, and were published in English.
DATA EXTRACTION AND SYNTHESIS
From records that underwent full-text review, 2 reviewers independently abstracted data and assessed the risk of bias. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline was followed. Eligible studies were included in the meta-analysis and analyzed with a common and random-effects analysis. Studies not included in the meta-analysis were summarized descriptively.
MAIN OUTCOMES AND MEASURES
The primary outcome was change in the incidence rate of pediatric diabetes during vs before the COVID-19 pandemic. The secondary outcome was change in the incidence rate of DKA among youths with new-onset diabetes during the pandemic.
RESULTS
Forty-two studies including 102 984 incident diabetes cases were included in the systematic review. The meta-analysis of type 1 diabetes incidence rates included 17 studies of 38 149 youths and showed a higher incidence rate during the first year of the pandemic compared with the prepandemic period (incidence rate ratio [IRR], 1.14; 95% CI, 1.08-1.21). There was an increased incidence of diabetes during months 13 to 24 of the pandemic compared with the prepandemic period (IRR, 1.27; 95% CI, 1.18-1.37). Ten studies (23.8%) reported incident type 2 diabetes cases in both periods. These studies did not report incidence rates, so results were not pooled. Fifteen studies (35.7%) reported DKA incidence and found a higher rate during the pandemic compared with before the pandemic (IRR, 1.26; 95% CI, 1.17-1.36).
CONCLUSIONS AND RELEVANCE
This study found that incidence rates of type 1 diabetes and DKA at diabetes onset in children and adolescents were higher after the start of the COVID-19 pandemic than before the pandemic. Increased resources and support may be needed for the growing number of children and adolescents with diabetes. Future studies are needed to assess whether this trend persists and may help elucidate possible underlying mechanisms to explain temporal changes.
Topics: Child; Humans; Incidence; Diabetes Mellitus, Type 1; Pandemics; Diabetes Mellitus, Type 2; COVID-19; Diabetic Ketoacidosis
PubMed: 37389869
DOI: 10.1001/jamanetworkopen.2023.21281 -
The Senior Care Pharmacist Jul 2023The objective of this systematic review was to evaluate adverse effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors in older people. Articles in PubMed and...
The objective of this systematic review was to evaluate adverse effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors in older people. Articles in PubMed and EBSCOhost-Medline databases between January 2011 and 2021 were analyzed. Search terms were SGLT2 inhibitor, SGLT2 inhibitors, geriatric/elderly/older people, and safety/ adverse drug reaction/tolerability. Meta-analyses, systematic reviews, review articles, journal clubs, articles that did not address the research question, excluded patients 65 years of age and older, had an updated article available, did not stratify by age group, or were a commentary on a cohort study were excluded. The search resulted in 113 articles. There were 62 duplicates removed, and 30 excluded based on the abstract. Of the 32 articles remaining, 19 were removed for not meeting the research question or meeting exclusion criteria. A total of 13 studies, including randomized controlled trials, cohort studies, and case reports, were assessed. Current evidence demonstrates that patients taking SGLT2 inhibitors and diuretics were more likely to experience volume depletion. Findings suggest that risk of UTI was highest when the patient's age is 75 years or older. Some studies indicated that risk of genital mycotic infection is prevalent in older people. Use of SGLT2 inhibitors in the older population was not associated with a higher risk of developing diabetic ketoacidosis. Use of SGLT2 inhibitors appears to be relatively safe in older people. The risk of side effects may be decreased by considering concomitant medications. Randomized controlled trials assessing safety of SGLT2 inhibitors in the older population is still warranted.
Topics: Aged; Humans; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37381139
DOI: 10.4140/TCP.n.2023.276 -
Research Synthesis Methods Sep 2023Rare events meta-analyses of randomized controlled trials (RCTs) are often underpowered because the outcomes are infrequent. Real-world evidence (RWE) from... (Meta-Analysis)
Meta-Analysis
Rare events meta-analyses of randomized controlled trials (RCTs) are often underpowered because the outcomes are infrequent. Real-world evidence (RWE) from non-randomized studies may provide valuable complementary evidence about the effects of rare events, and there is growing interest in including such evidence in the decision-making process. Several methods for combining RCTs and RWE studies have been proposed, but the comparative performance of these methods is not well understood. We describe a simulation study that aims to evaluate an array of alternative Bayesian methods for including RWE in rare events meta-analysis of RCTs: the naïve data synthesis, the design-adjusted synthesis, the use of RWE as prior information, the three-level hierarchical models, and the bias-corrected meta-analysis model. The percentage bias, root-mean-square-error, mean 95% credible interval width, coverage probability, and power are used to measure performance. The various methods are illustrated using a systematic review to evaluate the risk of diabetic ketoacidosis among patients using sodium/glucose co-transporter 2 inhibitors as compared with active-comparators. Our simulations show that the bias-corrected meta-analysis model is comparable to or better than the other methods in terms of all evaluated performance measures and simulation scenarios. Our results also demonstrate that data solely from RCTs may not be sufficiently reliable for assessing the effects of rare events. In summary, the inclusion of RWE could increase the certainty and comprehensiveness of the body of evidence of rare events from RCTs, and the bias-corrected meta-analysis model may be preferable.
Topics: Humans; Randomized Controlled Trials as Topic
PubMed: 37309821
DOI: 10.1002/jrsm.1648 -
Journal of Medical Virology Jun 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents may increase risk for a variety of post-acute sequelae including... (Meta-Analysis)
Meta-Analysis
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents may increase risk for a variety of post-acute sequelae including new-onset type 1 diabetes mellitus (T1DM). Therefore, this meta-analysis aims to estimate the risk of developing new-onset type 1 diabetes in children and adolescents as post-acute sequelae of SARS-CoV-2 infection. PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched up to March 20, 2023. A systematic review and subsequent meta-analyses were performed to calculate the pooled effect size, expressed as risk ratio (RR) with corresponding 95% confidence interval (CI) of each outcome based on a one-stage approach and the random-effects estimate of the pooled effect sizes of each outcome were generated with the use of the DerSimonian-Laird method. Eight reports from seven studies involving 11 220 530 participants (2 140 897 patients with a history of diagnosed SARS-CoV-2 infection and 9 079 633 participants in the respective control groups) were included. The included studies reported data from four U.S. medical claims databases covering more than 503 million patients (IQVIA, HealthVerity, TriNetX, and Cerner Real-World Data), and three national health registries for all children and adolescents in Norway, Scotland, and Denmark. It was shown that the risk of new-onset T1DM following SARS-CoV-2 infection in children and adolescents was 42% (95% CI 13%-77%, p = 0.002) higher compared with non-COVID-19 control groups. The risk of developing new-onset T1DM following SARS-CoV-2 infection was significantly higher (67%, 95% CI 32 %-112%, p = 0.0001) in children and adolescents between 0 and 11 years, but not in those between 12 and 17 years (RR = 1.10, 95% CI 0.54-2.23, p = 0.79). We also found that the higher risk for developing new-onset T1DM following SARS-CoV-2 infection only exists in studies from the United States (RR = 1.70, 95% CI 1.37-2.11, p = 0.00001) but not Europe (RR = 1.02, 95% CI 0.67-1.55, p = 0.93). Furthermore, we found that SARS-CoV-2 infection was associated with an elevation in the risk of diabetic ketoacidosis (DKA) in children and adolescents compared with non-COVID-19 control groups (RR = 2.56, 95% CI 1.07-6.11, p = 0.03). Our findings mainly obtained from US medical claims databases, suggest that SARS-CoV-2 infection is associated with higher risk of developing new-onset T1DM and diabetic ketoacidosis in children and adolescents. These findings highlight the need for targeted measures to raise public health practitioners and physician awareness to provide intervention strategies to reduce the risk of developing T1DM in children and adolescents who have had COVID-19.
Topics: Child; Humans; Adolescent; COVID-19; Diabetes Mellitus, Type 1; SARS-CoV-2; Diabetic Ketoacidosis; Post-Acute COVID-19 Syndrome; Cohort Studies
PubMed: 37264687
DOI: 10.1002/jmv.28833 -
Renal Failure Dec 2023The safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with diabetic kidney disease (DKD) is still controversial. This study aimed to... (Meta-Analysis)
Meta-Analysis Review
Comparative safety of sodium-glucose co-transporter 2 inhibitors in elderly patients with type 2 diabetes mellitus and diabetic kidney disease: a systematic review and meta-analysis.
The safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with diabetic kidney disease (DKD) is still controversial. This study aimed to analyze the safety of SGLT2 inhibitors in elderly patients with type 2 diabetes mellitus (T2DM) and DKD. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to March 2023. Randomized controlled trials (RCTs) were included. Data including patient characteristics and interesting outcomes were extracted, and the dichotomous data and continuous variables were evaluated using risk ratio (RR) with 95% confidence intervals (CIs) and mean difference (MD) with 95% CIs, respectively. A total of 14 RCTs with 59874 participants were finally included. There were 38,252 males (63.9%) and 21,622 females (36.1%). The patients' mean age was > 64.6 years. SGLT2 inhibitors could delay the further decline of estimated glomerular filtration rate (eGFR) when eGFR ≥ 60 ml/min/1.73m (MD: 2.36; 95%CI [1.15-3.57]). SGLT2 inhibitors in elderly patients with eGFR < 60 ml/min/1.73m (RR: 0.86; 95%CI [0.67-1.11]) may have a relatively increased risk of acute kidney injury compared to eGFR ≥ 60 ml/min/1.73m. SGLT2 inhibitors increased the incidence of genital mycotic infections (RR: 3.47; 95%CI [2.97-4.04]) and diabetic ketoacidosis (RR: 2.25; 95%CI [1.57-3.24]). Except for genital mycotic infections and diabetic ketoacidosis, other adverse reactions were few, indicating that SGLT2 inhibitors are relatively safe for elderly patients with T2DM and DKD. Safety and renoprotection may be diminished when SGLT2 inhibitors are used in elderly patients with eGFR < 60 ml/min/1.73m.
Topics: Male; Female; Humans; Aged; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Diabetic Nephropathies; Diabetic Ketoacidosis; Diabetes Mellitus, Type 2; Symporters; Glucose; Sodium; Hypoglycemic Agents
PubMed: 37246403
DOI: 10.1080/0886022X.2023.2217287