Huilin Tang

Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials.

To evaluate the comparative effects of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors on risk of bone fracture in patients with type 2 diabetes mellitus (T2DM).

Effect of Sodium–Glucose Cotransporter 2 Inhibitors on Diabetic Ketoacidosis Among Patients With Type 2 Diabetes: A Meta-analysis of Randomized Controlled Trials

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a novel class of antidiabetes drugs for the treatment of type 2 diabetes (T2D) (1). In addition to their hypoglycemic effect, SGLT2 inhibitors also offer several beneficial effects, such as weight loss and blood pressure reduction (1). However, the overall health benefits of these drugs needed to outweigh their possible side effects. Recently, cumulative evidence suggests that SGLT2 inhibitors may lead to diabetic ketoacidosis (DKA), which is a serious acute complication of diabetes (2,3). In May 2015, the U.S. Food and Drug Administration issued an updated drug safety communication warning about SGLT2 inhibitors potentially increasing the risk of DKA (4). As DKA is a rare adverse effect, the evidence from individual studies or simply pooling the numbers from multiple reports is generally weak. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) …

Sodium–glucose cotransporter 2 inhibitors and risk of adverse renal outcomes among type 2 diabetes patients: a network and cumulative meta‐analysis of randomized controlled trials

To compare the associations of individual sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors with adverse renal outcomes in patients with type 2 diabetes mellitus (T2DM).

Use of Epinephrine in Patients with Drug-Induced Anaphylaxis: An Analysis of the Beijing Pharmacovigilance Database

Background: Few studies assessing the use of epinephrine in drug-induced anaphylaxis (DIA) in the hospital setting are available. We utilized the Beijing Pharmacovigilance Database (BPD) to evaluate the appropriateness of epinephrine for DIA management. Methods: DIA cases collected in the BPD from January 2004 to December 2014 were adjudicated and analyzed for demographics, causative drugs, clinical signs, outcomes, initial treatment, route, dosing, and cardiovascular adverse events (CAE) of epinephrine. Results: DIA was primarily caused by antibiotics (38.4%), radiocontrast agents (11.9%), traditional Chinese medicine injections (10.9%), and chemotherapeutic drugs (10.3%). Only 708 (59.5%) patients received epinephrine treatment. Patients who received epinephrine were more likely to experience wheezing (p < 0.001) and respiratory arrest (p < 0.001). Among 518 patients with a complete record of the epinephrine administration route, the percentage of patients receiving it by intramuscular (IM) injection, subcutaneous (SC) injection, intravenous (IV) bolus injection, or IV continuous infusion was 16.9, 31.5, 43.5, and 8.1%, respectively. Among the 427 patients with a record of both the administration route and the dosing, an overdose was more likely with IV bolus (94.1%) in contrast to IM injection (56.6%; p < 0.001) or SC injection (43.7%; p < 0.001). Among the patients analyzed for CAE (n = 349), 17 patients accounted for 19 CAE, and 13 (76.5%) of these patients were overdosed with epinephrine. Conclusion: Underuse, inappropriate IV bolus use, and overdosing were the 3 major problems with epinephrine use in DIA in China. Educational training for health care professionals on the appropriate use of epinephrine in managing anaphylactic reactions is suggested.

Pioglitazone and bladder cancer risk: a systematic review and meta-analysis

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta‐analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose–response relationship with a generalized least‐squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever‐users of pioglitazone versus never‐users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time‐ (P = 0.003) and dose‐dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose‐ and time‐dependent manner. Patients with long‐term and high‐dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer.

Use of antihypertensive drugs and risk of keratinocyte carcinoma: A meta‐analysis of observational studies

Current epidemiologic evidence on the association between antihypertensive drugs and keratinocyte carcinoma (KC) risk is inconsistent. We sought to quantify this association by meta‐analysis of observational studies.

Phosphodiesterase type 5 inhibitors and risk of melanoma: A meta-analysis

Background: The association between phosphodiesterase type 5 (PDE5) inhibitors and melanoma risk is controversial. Objective: We quantify the association between use of PDE5 inhibitors and melanoma. Methods: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for studies that were conducted up to July 13, 2016, and evaluated the association between PDE5 inhibitors and skin cancer. Random effects meta‐analyses were used to calculate the adjusted odds ratio (OR) with the 95% confidence interval (CI). Results: Five observational studies were included. Compared with PDE5 inhibitor nonuse, PDE5 inhibitor use was slightly but significantly associated with an increased risk for development of melanoma (OR, 1.12; 95% CI, 1.03‐1.21) and basal cell carcinoma (OR, 1.14; 95% CI, 1.09‐1.19) but not squamous cell carcinoma. For melanoma risk, none of the prespecified factors (dose of PDE5 inhibitor, study design, and study region) significantly affected the results (P > .05). Our sensitivity analysis confirmed the stability of the results. Limitations: We included only observational studies, which had some heterogeneities and inconsistent controlling for potential confounders. Conclusions: Use of PDE5 inhibitors may be associated with a slightly increased risk for development of melanoma and basal cell carcinoma but not squamous cell carcinoma. However, further large well‐conducted prospective studies with adequate adjustment for potential confounders are required for confirmation.

Traditional Chinese medicine and drug-induced anaphylaxis: data from the Beijing pharmacovigilance database

Background Traditional Chinese medicine (TCM) is one of the major triggers for drug-induced anaphylaxis (DIA). Objective We aimed to use the Beijing pharmacovigilance database (BPD) to analyze TCM-induced DIAs in Beijing, China. Setting Drug allergy case reports from the BPD provided by the Beijing Center for Adverse Drug Reaction Monitoring. Method Drug allergy cases from January 2004 to December 2014 were adjudicated. DIA triggered by TCMs were analyzed and compared with those triggered by non-TCM drugs by calculating the reported risk ratio (RRR). We also calculated the RRRs based on severe DIA and death outcomes. Main outcome measure TCMs implicated in DIAs were identified and compared with non-TCM drugs. Results TCMs accounted for 1651 (18.2%) of the total 9074 allergic cases, in which 84.4% (1393/1651) were triggered by injections. Of the TCM allergic cases, 8.5% (141) were DIAs and 7.3% (120) were severe DIAs, and three patients died from injections. The RRR between TCMs and non-TCM-induced DIAs was 0.63. When anaphylactic cases were compared between TCMs to the top four non-TCM drug triggers, RRRs were 0.73 (95% CI 0.61–0.87) for antibiotics, 0.36 (95% CI 0.29–0.44) for radiocontrast agents, 0.55 (95% CI 0.43–0.68) for chemotherapeutics, and 0.29 (95% CI 0.23–0.37) for biologics. Compared to TCM oral or topic formulations, TCM injections had higher RRRs in each of the above comparisons. Conclusion TCM was associated with a decreased risk of DIA compared to non-TCM drugs in drug allergy cases, and the risk was higher for TCM injections.

Cancer risk in the EMPA-REG OUTCOME trial. Reply to Shaikh AMY [letter] and Kohler S, Lee J, George JT et al [letter]

To the Editor: We strongly but respectfully disagree with the letter by Dr. Shaikh [1] regarding an issue with the reporting of the number of cases of bladder cancer from the EMPA-REG OUTCOME Trial [2] in our meta-analysis of sodium–glucose cotransporter 2 (SGLT2) inhibitors and risk of cancer [3]. Since 2007, Section 801 of the Food and Drug Administration (FDA) Amendments Act (FDAAA) requires the submission of summary results, including adverse events for clinical trials of FDA-regulated drugs, to the ClinicalTrials.gov databank (www.ClinicalTrials.gov) [4]. As stated in our article, ‘If cancer events were not reported in the manuscripts, data from regulatory submissions or the ‘Serious adverse events’ section on ClinicalTrials.gov were extracted’ [3]. Our study included only confirmed cases of bladder cancer, classified as ‘bladder cancer’, ‘bladder cancer transitional cell carcinoma’ and ‘bladder cancer recurrent’, which were identified according to the Medical Dictionary for Regulatory Activities (MedDRA) (such information was also presented in electronic supplementary material (ESM) Table 2 of our article) [3]. Hence, the number of incident cases of bladder cancer in our article was correctly extracted from ClinicalTrials.gov, with the current database for the EMPA-REG OUTCOME Trial (ClinicalTrial.gov registration no. NCT01131676, accessed 9 August 2017) still showing six cases of bladder cancer, two cases of bladder transitional cell carcinoma, and one recurrent case of bladder cancer in the empagliflozin groups, and zero cases in the placebo group (Table 1). We appreciate the updated data from the US FDA provided by Dr. Shaikh [1], which is also highlighted in a second letter by Kohler et al [5], although the crude comparisons of case numbers made in this second letter could be misleading owing to the small sample size [5]. Even based on the intention-totreat data or on-treatment data sets provided by Kohler and colleagues [5], we still observed a non-significant trend towards increased risk of bladder cancer in the pooled empagliflozin groups compared with the placebo groups; the relative risks were 1.20 (95% CI 0.42, 3.40) for the intentionto-treat data set and 1.83 (95% CI 0.51, 6.56) for the ontreatment data set. In addition, we feel it is important to note that the actual number of confirmed cancer cases would continue to accumulate during an extended post-trial period of the EMPA-REG OUTCOME Trial. However, given that participants in this trial were no longer receiving randomly assigned treatments, a crude comparison of accrued case numbers on an intention-to-treat basis tends to lead to a biased and incorrect estimate of drug effect owing to potential bias and confounding. Hence, we stand by our statement that ‘there is some evidence suggesting that SGLT2 inhibitors (especially empagliflozin) might increase risk of bladder cancer’, rather than conclusive evidence demonstrating a causal relationship. * Jiali Han jialhan@iu.edu