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

SCI(E)[email protected]

Use of Antihypertensive Drugs and Risk of Malignant Melanoma: A Meta-analysis of Observational Studies

Introduction Several antihypertensive drugs are photosensitizing and may promote the development of malignant melanoma (MM), but evidence remains inconsistent. We sought to quantify the association between use of antihypertensive drugs and MM risk. Methods We systematically searched PubMed, Embase, and CENTRAL from inception to August 17, 2017 to identify observational studies that reported the MM risk associated with the use of antihypertensive drugs. A random-effects meta-analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI). Results Overall, we included eight observational studies (two cohort studies and six case–control studies). Compared with non-use, use of diuretics (OR 1.10; 95% CI 1.03–1.17) or β-adrenergic blocking agents (OR 1.19; 95% CI 1.04–1.37) was significantly associated with increased risk of MM. The use of angiotensin-converting enzyme inhibitors (OR 1.08; 95% CI 0.95–1.23), angiotensin II receptor blockers (OR 1.12; 95% CI 0.95–1.31), and calcium channel blockers (OR 1.12; 95% CI 0.72–1.74) was not significantly associated with increased risk of MM. Conclusions Current evidence from observational studies suggests that use of diuretics or β-adrenergic blocking agents may be associated with increased risk of MM. Further large well-conducted prospective studies are required to confirm our findings

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

Aims/hypothesis The association between sodium–glucose cotransporter 2 (SGLT2) inhibitors and the risk of cancer in individuals with type 2 diabetes remains uncertain. This study aimed to evaluate the risk of cancer associated with SGLT2 inhibitor treatment of type 2 diabetes. Methods We systematically searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to 15 February 2017 to identify eligible randomised controlled trials (RCTs) that report cancer events in individuals with type 2 diabetes treated with SGLT2 inhibitors for at least 24 weeks. We performed pairwise and network meta-analyses as well as a cumulative meta-analysis to calculate ORs and 95% CIs. Results In total, 580 incidences of cancer among 34,569 individuals were identified from 46 independent RCTs with a mean trial duration of 61 weeks. When compared with comparators (placebo or other active glucose-lowering treatments), SGLT2 inhibitors were not significantly associated with an increased risk of overall cancer (OR 1.14 [95% CI 0.96, 1.36]). For pre-specified cancer types, the risk of bladder cancer might be increased with SGLT2 inhibitors (OR 3.87 [95% CI 1.48, 10.08]), especially empagliflozin (OR 4.49 [95% CI 1.21, 16.73]). Interestingly, canagliflozin might be protective against gastrointestinal cancers (OR 0.15 [95% CI 0.04, 0.60]). Conclusions/interpretation Current evidence from short-term RCTs did not indicate a significantly increased risk of overall cancer among individuals with type 2 diabetes using SGLT2 inhibitors. Given the short-term trial durations and uncertainty of evidence, future long-term prospective studies and post-marketing surveillance studies are warranted

Meta-Analysis of Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Outcomes and All-Cause Mortality Among Patients With Type 2 Diabetes Mellitus

The benefit or risk of sodium glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus has not been established. We aimed to assess the comparative CV safety and mortality risk associated with the use of SGLT2 inhibitors. PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov were systematically searched up to January 27, 2016, to identify randomized controlled trials (RCTs) with the use of SGLT2 inhibitors of at least 24 weeks of duration. The primary outcomes included all-cause mortality and major adverse cardiovascular events. A random-effects network meta-analysis was performed to calculate the odds ratio (OR) with 95% CI. We identified 37 eligible trials involving 29,859 patients that compared 3 SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to placebo and other active antidiabetic treatments. Of all direct and indirect comparisons, only empagliflozin compared with placebo was significantly associated with lower risk of all-cause mortality (OR 0.67, 95% CI 0.56 to 0.81) and major adverse cardiovascular events (OR 0.81, 95% CI 0.70 to 0.93). However, the significant effect of empagliflozin was largely driven by one large randomized trial (EMPA-REG OUTCOME trial). Neither dapagliflozin nor canagliflozin was significantly associated with any harm. In conclusion, current RCT evidence suggests that 3 common SGLT2 inhibitors are not associated with increased risk of all-cause mortality and CV outcomes when used to treat patients with type 2 diabetes mellitus. Although empagliflozin may have a protective effect, further confirmative data from rigorous RCTs are needed

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

Purpose 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. Methods We systematically reviewed observational studies published through August 2016 and reported the KC risk (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) associated with antihypertensive drugs, including diuretics, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta‐adrenergic blocking agents (β‐blockers), and calcium channel blockers (CCBs). Random‐effects meta‐analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI). Results Ten eligible studies were included. Compared with nonuse, diuretic use was significantly associated with increased risk of both BCC (OR, 1.10; 95% CI, 1.01‐1.20) and SCC (OR, 1.40; 95% CI, 1.19‐1.66). Use of β‐blockers or CCBs was associated with increased risk of BCC (but not SCC); the OR with β‐blockers was 1.09 (95% CI, 1.04‐1.15) and with CCBs was 1.15 (95% CI, 1.09‐1.21). Use of ACE inhibitors or ARBs was associated with decreased risk of both BCC (OR, 0.53; 95% CI, 0.39‐0.71) and SCC (OR, 0.58; 95% CI, 0.42‐0.80) in high‐risk individuals. Conclusions Current evidence indicates that use of diuretics might be associated with increased risk of KC, while ACE inhibitors or ARBs might be associated with decreased risk in high‐risk individuals. β‐blockers or CCBs might be positively associated with BCC risk. Further postmarketing surveillance studies and investigations to clarify the possible underlying mechanisms are warranted

Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials

Aim 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). Methods PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were searched for studies published up to May 24, 2016, without language or date restrictions. Randomized trials that reported at least 1 renal-related adverse outcome in patients with T2DM treated with SGLT2 inhibitors were included. Pairwise and network meta-analyses were carried out to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and a cumulative meta-analysis was performed to assess the robustness of evidence. Results In total, we extracted 1334 composite renal events among 39 741 patients from 58 trials, and 511 acute renal impairment/failure events among 36 716 patients from 53 trials. Dapagliflozin was significantly associated with a greater risk of composite renal events than placebo (OR 1.64, 95% CI 1.26-2.13). Empagliflozin seemed to confer a lower risk than placebo (OR 0.63, 95% CI 0.54-0.72), canagliflozin (OR 0.48, 95% CI 0.29-0.82) and dapagliflozin (OR 0.38, 95% CI 0.28-0.51). With regard to acute renal impairment/failure, only empagliflozin was significantly associated with a lower risk than placebo (OR 0.72, 95% CI 0.60-0.86). The cumulative meta-analysis indicated the robustness of our significant findings. Conclusions The present meta-analysis indicated that dapagliflozin may increase the risk of adverse renal events, while empagliflozin may have a protective effect among patients with T2DM. Further data from large well-conducted randomized controlled trials and a real-world setting are warranted

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

Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials

Aims/hypothesis By analysing available evidence from randomised controlled trials (RCTs), we aimed to examine whether and to what extent sodium–glucose cotransporter 2 (SGLT2) inhibitors affect serum electrolyte levels in type 2 diabetes patients. Methods We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov up to 24 May 2016 for published RCTs of SGLT2 inhibitors that reported changes in serum electrolyte levels. Weighted mean differences (WMD) between each SGLT2 inhibitor and placebo were calculated using a random-effects model. Dose-dependent relationships for each SGLT2 inhibitor were evaluated using meta-regression analysis. Results Eighteen eligible RCTs, including 15,309 patients and four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin and ipragliflozin) were evaluated. In patients without chronic kidney disease, each SGLT2 inhibitor significantly increased serum magnesium levels compared with placebo (canagliflozin: WMD 0.06 mmol/l for 100 mg and 0.09 mmol/l for 300 mg; dapagliflozin: WMD 0.1 mmol/l for 10 mg; empagliflozin: WMD 0.04 mmol/l for 10 mg and 0.07 mmol/l for 25 mg; and ipragliflozin: WMD 0.05 mmol/l for 50 mg). Canagliflozin increased serum magnesium in a linear dose-dependent manner (p = 0.10). Serum phosphate was significantly increased by dapagliflozin. Serum sodium appeared to significantly differ by SGLT2 inhibitor type. No significant changes in serum calcium and potassium were observed. Findings were robust after including trials involving patients with chronic kidney disease. Conclusions/interpretation SGLT2 inhibitors marginally increased serum magnesium levels in type 2 diabetes patients indicating a drug class effect. Further investigations are required to examine the clinical significance of elevated magnesium levels in individuals with type 2 diabetes

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

Drug-induced anaphylaxis in China: a 10 year retrospective analysis of the Beijing Pharmacovigilance Database

Background Few studies on the causes of drug-induced anaphylaxis (DIA) in the hospital setting are available. Objective We aimed to use the Beijing Pharmacovigilance Database (BPD) to identify the causes of DIA in Beijing, China. Setting Anaphylactic case reports from the BPD provided by the Beijing Center for Adverse Drug Reaction Monitoring. Method DIA cases collected by the BPD from January 2004 to December 2014 were adjudicated. Cases were analyzed for demographics, causative drugs and route of administration, and clinical signs and outcomes. Main outcome measure Drugs implicated in DIAs were identified and the signs and symptoms of the DIA cases were analyzed. Results A total of 1189 DIA cases were analyzed. The mean age was 47.6 years, and 732 (61.6%) were aged from 18 to 59 years. A total of 627 patients (52.7%) were females. There was a predominance of cardiovascular (83.8%) followed by respiratory (55.4%), central nervous (50.1%), mucocutaneous (47.4%), and gastrointestinal symptoms (31.3%). A total of 249 different drugs were involved. DIAs were mainly caused by antibiotics (39.3%), traditional Chinese medicines (TCM) (11.9%), radiocontrast agents (11.9%), and antineoplastic agents (10.3%). Cephalosporins accounted for majority (34.5%) of antibiotic-induced anaphylaxis, followed by fluoroquinolones (29.6%), beta-lactam/beta-lactamase inhibitors (15.4%) and penicillins (7.9%). Blood products and biological agents (3.1%), and plasma substitutes (2.1%) were also important contributors to DIAs. Conclusion A variety of drug classes were implicated in DIAs. Patients should be closely monitored for signs and symptoms of anaphylaxis when medications are administered especially with antibiotics, TCM, radiocontrast and antineoplastic agents