Clinical Adverse Events Associated with Sodium-Glucose Cotransporter 2 Inhibitors: A Meta-Analysis Involving 10 Randomized Clinical Trials and 71,553 Individuals

2021 ◽  
Author(s):  
Donna Shu-Han Lin ◽  
Jen-Kuang Lee ◽  
Wen-Jone Chen
Keyword(s):  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Genital Infection ◽  
High Dose ◽  
Atherosclerotic Cardiovascular Disease ◽  
Sodium Glucose Cotransporter ◽  
Safety Outcomes ◽  
Underlying Diseases

Abstract Objectives This meta-analysis aimed to investigate the occurrence of various adverse events (AEs) associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and to examine the level of risk of AEs in patients with different underlying diseases. Background SGLT2i are first-line antidiabetic agents with demonstrated cardiovascular benefits. Prior meta-analyses have examined AEs associated with these drugs in general, but such knowledge needs to be updated with the results of more recent trials. In addition, the occurrence of various AEs with different underlying diseases is unknown. Methods We conducted a quantitative meta-analysis of randomized controlled trials (RCTs) retrieved from the MEDLINE and EMBASE databases and the Cochrane library were searched on January 31 th, 2021. Outcomes of interest included 4 overall safety outcomes (AEs) and 12 specified safety outcomes. Further analyses were performed on various subgroups, which were defined based on the status of diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and congestive heart failure, and by the dosage of SGLT2i (high dose versus low dose). Results Our analysis included 10 eligible studies with a total of 71,553 participants. The meta-analysis showed that SGLT2i led to increased risks of genital infection (risk ratio [RR] 3.56, 95% confidence interval [CI] 2.84–4.46), urinary tract infection (RR 1.06, 95% CI 1.00–1.12), diabetic ketoacidosis (RR 2.23, 95% CI 1.36–3.63), and volume depletion (RR 1.14, 95% CI 1.06–1.23). However, the use of SGLT2i was associated with reduced risks of any serious AE (RR 0.92, 95% CI 0.90–0.94), acute kidney injury (AKI) (RR 0.84, 95% CI 0.77–0.91), and hyperkalemia (RR 0.84, 95% CI 0.72–0.99). Within the different subgroups, the risk of amputation was higher in patients with ASCVD than in those without (RR 1.44 vs. 0.96, P = 0.066). Conclusions The use of SGLT2i is generally safe. SGLT2i may be associated with increased risks of genital infection but is protective against AKI. Of note, the risk of amputation was higher in patients with ASCVD. The key to the safe use of SGLT2i lies in the identification of high-risk populations and close surveillance of patients after treatment.

scholarly journals The safety and efficacy of SDLT-2 (Sodium-glucose co-transporter 2) inhibitor versus placebo in the treatment of heart failure in patients with or without T2DM (Type 2 diabetes mellitus): A Systemic Review and Meta-analysis.

2020 ◽  
Author(s):  
Qian Zhang ◽  
Xiaofei Wang ◽  
Peipei Ge ◽  
Aizhen Hu ◽  
Xuexun Li
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Sglt2 Inhibitor ◽  
Systemic Review ◽  
Cochrane Library ◽  
Volume Depletion ◽  
Patients With Heart Failure ◽  
Safety Outcomes

Abstract Background Sodium-glucose co-transporter 2 (SGLT2) inhibitor which is a type of drug used for the treatment of diabetes mellitus, has been reported by many trials that it could be beneficial for patients with established heart failure. A meta-analysis on this subject could obtain more reliable estimates of the efficacy and safety outcomes. Methods A systematic review and meta-analysis of randomized, placebo-controlled trials of SGLT2 inhibitor in patients with heart failure was conducted. We searched PubMed, Cochrane Library, and Web of Science for trials published from inception to March, 2018. PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) was used to conduct the review. For quality assessment of included studies. The methodological quality of the included trials was assessed using the Cochrane tool for assessing randomized clinical trials (RCT). Efficacy outcomes included hospitalization for heart failure and all-cause death. Safety outcomes consisted of serious adverse event (SAE) and volume depletion. Results We included data from 5 identified studies and 8775 patients (aged 64.9, female 29.8%). A total of 3930 (44.8%) patients were known to have diabetes mellitus. Compared with placebo, SGLT2 inhibitor decrease the incidence of hospitalization for heart failure (RR 0.692; 95%CI, 0.611-0.784 P<0.001), and all-cause death (RR 0.824; 95%CI, 0.736-0.922 P=0.001). The incidence of SAE in patients with a treatment of SGLT2 inhibitor was low (RR 0.869; 95%CI, 0.779-0.970 P=0.012). SGLT2 inhibitor didn’t increase the incidence of volume depletion (RR1.165, 95%CI, 0.977-1.390 P=0.089). Conclusion Our results confirm that SGLT2 inhibitor is effective and safe for patients with heart failure regardless of presence of diabetes mellitus.

Different Doses of Erenumab for Preventive Treatment of Episodic Migraine: A Systematic Review and Network Meta-Analysis

2020 ◽  
Author(s):  
Yanbo Yang ◽  
Mingjia Chen ◽  
Zilan Wang ◽  
Yue Sun ◽  
Fan Jiang ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Response Rate ◽  
Meta Analysis ◽  
Preventive Treatment ◽  
Episodic Migraine ◽  
Cochrane Library ◽  
Migraine Treatment ◽  
Increased Risk ◽  
Significant Difference ◽  
Safety Outcomes

Abstract Background Erenumab is a novel monoclonal calcitonin gene–related peptide receptor antibody that is used for the preventive treatment of migraine.Objectives To evaluate overall safety and efficacy and dose-response relationship of erenumab in patients with episodic migraine and patients with prior migraine treatment failures.Methods We searched randomized clinical trials on PUBMED, EMBASE database, and Cochrane Library database. A pair-wise meta-analysis and Bayesian network analysis were performed.Results For efficacy outcomes, the network meta-analysis suggests that compared with erenumab 70 mg, participants received erenumab 140 mg reported significantly decreased MSMD and increased 50% response rate, and erenumab was most likely to be ranked first for MMD, MSMD and 50% response rate. For safety outcomes, the network meta-analysis has found no significant difference between the 70 mg group and the 140 mg group measured by AE and SAE. For patients with ≥2 treatment failures, 140mg erenumab group, patients with ≥2 treatment failures reported significantly reduced MMD and MSMD, increased 50%, and 75% response rate, compared with placebo. For safety outcomes, no significant difference was found between 140 mg erenumab group and the placebo group.Conclusion Erenumab was effective in patients with episodic migraine. 140 mg erenumab was associated with better efficacy outcomes without increased risk for developing adverse events compared with 70 mg erenumab, and 140 mg erenumab was effective in patients with prior migraine treatment failures.Registration number: CRD42020198985

Clinical Adverse Events of High-Dose vs Low-Dose Sodium–Glucose Cotransporter 2 Inhibitors in Type 2 Diabetes: A Meta-Analysis of 51 Randomized Clinical Trials

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Fang-Hong Shi ◽  
Hao Li ◽  
Jiang Yue ◽  
Yi-Hong Jiang ◽  
Zhi-Chun Gu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Adverse Events ◽  
Low Dose ◽  
Randomized Clinical Trials ◽  
Sglt2 Inhibitors ◽  
High Dose ◽  
Sodium Glucose Cotransporter ◽  
Subgroup Analyses

Abstract Aims The aims of this work are to assess the clinical adverse events (AEs) of high-dose vs low-dose sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) in patients with type 2 diabetes mellitus (T2DM). Methods We searched MEDLINE, EMBASE, and Cochrane Library from January 1, 2006 to March 10, 2020, for identifying eligible randomized clinical trials (RCTs) that reported AEs by high-dose and low-dose SGLT2 inhibitors in T2DM patients. Random-effects models was used to obtain summary relative risks (RRs) with associated 95% CIs. Prespecified subgroup analyses according to individual SGLT2 inhibitors and follow-up duration, and leave-one-out sensitivity analysis were conducted. Results A total of 51 RCTs involving 24 371 patients (12 208 received high-dose and 12 163 received low-dose SGLT2 inhibitors) were included. Overall, the heterogeneity among included studies was relatively low (I2 &lt; 50% for each outcome). No significant differences between high-dose and low-dose SGLT2 inhibitors were observed for overall safety (including any AEs, serious AEs, AEs leading to discontinuation, and death) and specified safety (including infections and infestations, musculoskeletal disorders, gastrointestinal disorders, osmotic diuresis-related AEs, volume-related AEs, renal-related AEs, and metabolism and nutrition), except for a mild increase in risk for AEs related to study drugs (RR: 1.08; 95% CI, 1.01-1.16) that mainly derived from canagliflozin (RR: 1.17; 95% CI, 1.05-1.30). Subgroup analyses were consistent with the primary outcomes. Conclusions This study provided substantial evidence that AEs of SGLT2 inhibitors were not dose related.

scholarly journals A Meta-Analysis of the Efficacy of Panax Ginseng on Menopausal Women’s Sexual Function

2018 ◽  
Vol 7 (1) ◽  
pp. 124-133 ◽  
Author(s):  
Zahra Ghorbani ◽  
Mojgan Mirghafourvand
Keyword(s):  
Sexual Dysfunction ◽  
Adverse Events ◽  
Sexual Function ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Random Effect ◽  
Cochrane Library ◽  
Control Group ◽  
Placebo Control ◽  
Significant Difference

Objectives: An increase in life expectancy results in the aging population growth. This study was designed to evaluate the efficacy and adverse events of ginseng that could be used as a herbal medicine in women with sexual dysfunction. Materials and Methods: The authors of this study searched Cochrane Library, MEDLINE, Web of Science, Embase, Scopus, ProQuest, Google Scholar, and Persian databases without a time limitation until May 2018 and examined all the randomized clinical trials (RCTs) that compared the effect of different types of ginseng on sexual function of menopausal women as compared to the placebo controls. The Cochrane risk of bias tool was used to assess the methodological quality of the included studies. The heterogeneity was determined using the I2 index. In addition, standardized mean difference (SMD) was used instead of mean differences (MD) and a random effect was reported instead of fixed effect in meta-analysis. Results: The eligibility criteria were found in five RCTs. All the included studies were placebo-controlled. Two trials had a parallel design while three studies used a crossover design. Although four trials indicated that ginseng significantly improved sexual function, they didn’t report any treatment effect compared to the placebo group. Based on the results of meta-analysis obtained from five studies including 531 women, there was no statistically significant effect of ginseng on female sexual dysfunction (FSD) compared to the placebo control group (SMD: 0.26; 95% CI: -0.26 to 0.76). Nonetheless, there was a considerable heterogeneity among the studies (I2 = 81%; P < 0.0001). Moreover, all the included studies assessed adverse events, but in three of the RCTs, there was no significant difference between the placebo and ginseng groups. Conclusions: The evidence regarding ginseng as a therapeutic agent for sexual dysfunction is unjustifiable. Rigorous studies seem warranted in this respect.

scholarly journals Role of Statins in the Primary Prevention of Atherosclerotic Cardiovascular Disease and Mortality in the Population with Mean Cholesterol in the Near-Optimal to Borderline High Range: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Bishnu M. Singh ◽  
Hari K. Lamichhane ◽  
Sanjay S. Srivatsa ◽  
Prabhat Adhikari ◽  
Bikash J. Kshetri ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Adverse Events ◽  
Statin Therapy ◽  
Meta Analysis ◽  
Density Lipoprotein ◽  
Cochrane Library ◽  
Atherosclerotic Cardiovascular Disease ◽  
Serious Adverse Events ◽  
Increased Risk ◽  
High Range

AbstractObjectiveThe objective of this meta-analysis was to analyze the benefits and harms of treating the population with statins in those having mean low-density lipoprotein cholesterol (LDL-C) in the near-optimal (100 to 129 mg/dl) to borderline high (130 to 159 mg/dl) range and free of cardiovascular disease (CVD). Methods: We searched PubMed, PubMed Central, Cochrane Library, and Google Scholar databases for randomized controlled trials (RCTs) published between 1994 and July 2020. We included RCTs with greater than 90% of participants free of CVD. Two reviewers independently screened the articles using the Covidence software, assessed the methodological quality using the risk of bias 2 tool, and analyzed the data using the RevMan 5.4 software. Results: Eleven trials were included. Statin therapy was associated with a decreased risk of myocardial infarction (RR=0.56, 95% CI: 0.47 to 0.67), major cerebrovascular events (RR=0.78, 95% CI: 0.63 to 0.96), major coronary events (RR=0.67, 95% CI: 0.57 to 0.80), composite cardiovascular outcome (RR=0.71, 95% CI: 0.62 to 0.82), revascularizations (RR=0.65, 95% CI: 0.57 to 0.74), angina (RR=0.76, 95% CI: 0.63 to 0.92) and hospitalization for cardiovascular causes (RR=0.74, 95% CI: 0.64 to 0.86). There was no benefit associated with statin therapy for cardiovascular mortality and coronary heart disease mortality. All-cause mortality benefit with statin therapy was seen in the population with diabetes and increased risk of CVD. Statin therapy was associated with no significant increased risk of myalgia, creatine kinase elevation, rhabdomyolysis, myopathy, incidence of any cancer, incidence of diabetes, withdrawal of the drug due to adverse events, serious adverse events, fatal cancer, and liver enzyme abnormalities. Conclusion: Statin therapy was associated with a reduced risk of cardiovascular disease and procedures without increased risk of harm in populations with mean LDL-C near-optimal to the borderline high range without prior atherosclerotic cardiovascular disease.

scholarly journals Erenumab safety and efficacy in migraine: a systematic review and meta-analysis of randomized clinical trials

2018 ◽  
Author(s):  
Changyu Zhu ◽  
Jianmei Guan ◽  
Hua Xiao ◽  
Weinan Luo ◽  
Rongsheng Tong
Keyword(s):  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Preventive Treatment ◽  
Pooled Analysis ◽  
Cochrane Library ◽  
Serious Adverse Events ◽  
Increased Risk ◽  
Specific Medication ◽  
Mean Differences

Abstract Background: Erenumab is a new medicine approved lately in the US for the preventive treatment of migraine in adults. We aimed to conduct a meta-analysis to evaluate the efficacy and safety of erenumab in patients with migraine. Methods: The electronic database composed of PubMed, Embase and Cochrane library was independently retrieved by two reviewers. Only randomized controlled trials (RCTs) that compared between placebo and erenumab were included in this analysis. mean differences (MDs) and Pooled risk ratios (RRs) as well as their corresponding 95% confidence intervals (CIs) were calculated for continuous and dichotomous data, respectively. Results: Total five RCTs representing 2928 patients were included. Pooled analysis showed significant reductions of the 50% reduction(RR 1.55; 95%CI,1.35 to 1.77; P < 0.00001; I²=49%). In addition, the mean monthly migraine days (MMMDs) from baseline in the erenumab group compared with placebo (MD -1.32, 95%CI, -1.73 to -0.91; P < 0.00001; I²=100%) and migraine-specific medication days (MSMDs) from baseline (MD -1.41; 95%CI, -1.80 to -1.02; P＜0.00001; I²=100%) were significantly increased for the erenumab group compared with placebo. Furthermore, there was significant reduction of MSMDs from baseline in 140mg erenumab group compared to 70mg (MD=0.55; 95%CI:0.54 to 0.66; Z =10.95; P<0.00001; I²=90% ). Finally, there were no significant differences between erenumab group and placebo of any adverse events and serious adverse events. Conclusion: Among patients with migraine, both 70mg and 140mg erenumab are associated with reduction of MMMDs, MSMDs from baseline and increased rate of 50% reduction without increased risk of any adverse events and serious adverse events.

scholarly journals Adverse Events Associated With Anti-IL-23 Agents: Clinical Evidence and Possible Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Ru ◽  
Xiaojie Ding ◽  
Ying Luo ◽  
Hongjin Li ◽  
Xiaoying Sun ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Event ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Cochrane Library ◽  
The Cochrane Library ◽  
Specific Symptoms

BackgroundAnti-interleukin (IL)-23 agents are widely used for autoimmune disease treatment; however, the safety and risks of specific symptoms have not been systematically assessed.ObjectivesThe aim of this study was to summarize the characteristics and mechanisms of occurrence of five immunological and non-immunological adverse events caused by different anti-IL-23 agents.MethodsThe Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched for eligible randomized clinical trials published from inception through May 1, 2020. Randomized clinical trials that reported at least one type of adverse event after treatment were included, regardless of sex, age, ethnicity, and diagnosis. Two investigators independently screened and extracted the characteristics of the studies, participants, drugs, and adverse event types. The Cochrane Handbook was used to assess the methodological quality of the included randomized clinical trials. Heterogeneity was assessed using the I2 statistic. Meta-regression was applied to determine the sources of heterogeneity, and subgroup analysis was used to identify the factors contributing to adverse events.ResultsForty-eight studies were included in the meta-analysis, comprising 25,624 patients treated with anti-IL-23 agents. Serious immunological or non-immunological adverse events were rare. Anti-IL-12/23-p40 agents appeared to cause adverse events more easily than anti-IL-23-p19 agents. The incidence of cancer did not appear to be related to anti-IL-23 agent treatment, and long-term medication could lead to mental diseases. The prevention of complications should be carefully monitored when administered for over approximately 40 weeks to avoid further adverse reactions, and the incidence of infection was the highest among general immunological adverse events.ConclusionsThe application of anti-IL-23 agents induced a series of immunological and non-immunological adverse events, but these agents tend to be well-tolerated with good safety profiles.

Efficacy and Safety of Methylnaltrexone for the Treatment of Opioid-Induced Constipation: A Meta-analysis of Randomized Controlled Trials

2020 ◽  
Author(s):  
Ying-Ying Zhang ◽  
Rong Zhou ◽  
Wan-Jie Gu
Keyword(s):  
Abdominal Pain ◽  
Adverse Events ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Controlled Trials ◽  
Efficacy And Safety ◽  
Safety Outcome ◽  
Randomized Controlled ◽  
Safety Outcomes

Abstract Background: Opioid-induced constipation (OIC) is a distressing side effect during opioid analgesia and is mainly mediated by gastrointestinal μ opioid receptors. Methylnaltrexone, a peripheral μ opioid receptor antagonist with restricted ability to cross the blood-brain barrier, may alleviate OIC without reversing analgesia. We performed a meta-analysis to assess the efficacy and safety of methylnaltrexone for the treatment of OIC.Methods: We searched PubMed, Embase, and Cochrane Library for randomized controlled trials that compared methylnaltrexone with placebo for the treatment of OIC. The primary efficacy outcome was rescue-free bowel movement (RFBM) within 4 hours after the first dose. Secondary efficacy outcomes included RFBM within 24 hours after the first dose, RFBM ≥3 times per week, and need take rescue laxatives. The primary safety outcome was any adverse events. Secondary safety outcomes included abdominal pain, diarrhea, nausea, vomiting, and flatulence. Relative risks (RR) and 95% confidence interval (CI) were pooled using random-effects model with the intention-to-treat principle. We used the GRADE approach to assess the certainty of the evidence.Results: Eight trials with 2,034 participants were included. Compared with placebo, methylnaltrexone significantly increased RFBM within 4 hours after the first dose (8 trials; 1,833 participants; RR 3.74, 95% CI 3.02-4.62; I2 = 0%; high-certainty evidence), RFBM within 24 hours after the first dose (2 trials; 614 participants; RR 1.98, 95% CI 1.52-2.58; I2 = 9%; moderate-certainty evidence), and RFBM ≥3 times per week (3 trials; 1,396 participants; RR 1.33, 95% CI 1.17-1.52; I2 = 0%; moderate-certainty evidence) and decreased need to take rescue laxatives (3 trials; 807 participants; RR 0.73, 95% CI 0.63-0.85; I2 = 0%; moderate-certainty evidence). For safety outcomes, there was no difference in any adverse events between the two groups (8 trials; 2,034 participants; RR 1.11, 95% CI 0.99-1.23; I2 = 34%; moderate-certainty evidence), including diarrhea, nausea, vomiting, and flatulence; but for the most commonly reported adverse events, the abdominal pain was higher in methylnaltrexone group than that in placebo group (6 trials; 1,813 participants; RR 2.30, 95% CI 1.29-4.08; I2 = 62%; moderate-certainty evidence).Conclusions: Methylnaltrexone is an effective and safe drug for treating OIC. But the safety of abdominal pain should be considered.Trial registration: PROSPERO (CRD42020187290).

scholarly journals Optimal treatment strategy of fremanezumab in migraine prevention: a systematic review with network meta-analysis of randomized clinical trials

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
I-Hsin Huang ◽  
Po-Chien Wu ◽  
Ya-Han Lee ◽  
Yi-No Kang
Keyword(s):  
Adverse Events ◽  
Treatment Strategy ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Reduction Rate ◽  
High Dose ◽  
Efficacy And Safety ◽  
Serious Adverse Events ◽  
Mean Differences

Abstract Identifying the optimal fremanezumab treatment strategy is crucial in treating patients with migraines. The optimal strategy was investigated by assessing the cumulative 50% reduction rate (50%CRR), cumulative 75% reduction rate (75%CRR), reduction in the number of migraine days, treatment-related adverse events, and serious adverse events in patients treated with fremanezumab 225 mg monthly (225 mg), 675 mg monthly (675 mg), 900 mg monthly (900 mg), a single high dose of 675 mg (S675mg), 675 mg at baseline with 225 mg monthly (675/225 mg), and placebo. Biomedical databases were searched for randomized controlled trials on this topic, and data were individually extracted. Risk ratios and mean differences were used to present the pooled results. The surface under the cumulative ranking curve (SUCRA) was used to determine the effects of the medication strategies of fremanezumab. Five trials (n = 3404) were used to form a six-node network meta-analysis. All fremanezumab medication strategies displayed significantly higher cumulative 50% reduction rates than the placebo. The SUCRA revealed that treatment with 675 mg yielded the highest 50%CRR value (mean rank = 2.5). S675 mg was the only treatment with significantly higher 75%CRR reduction rate than placebo, whereas the SUCRA for 225 mg displayed the highest mean rank (2.2). Moreover, 225 mg (mean rank = 2.2) and S675 mg (mean rank = 2.2) presented lower probabilities of serious adverse events. Collectively, S675mg and 225 mg exhibited the optimal balance between efficacy and safety within three months. Long-term efficacy and safety remain unclear, and future studies should further evaluate the long-term outcomes.

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