Post-Authorization Safety Studies of Acute Liver Injury and Severe Complications of Urinary Tract Infection in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

INTRODUCTION: At the time of dapagliflozin's approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. OBJECTIVE: To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012-February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. RESULTS: In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59-1.24) and for sUTI was 0.76 (0.60-0.96) in females and 0.74 (0.56-1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. CONCLUSIONS: These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs.

Post-Authorization Safety Study of Hospitalization for Acute Kidney Injury in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

INTRODUCTION: Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. OBJECTIVE: The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. RESULTS: In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22-0.86]; HIRD, 0.76 [95% CI, 0.62-0.93]; Medicare, 0.69 [95% CI, 0.59-0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62-0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. CONCLUSIONS: This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. STUDY REGISTRATION: European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082.

Pancreatitis Incidence in the Exenatide BID, Exenatide QW, and Exenatide QW Suspension Development Programs: Pooled Analysis of 35 Clinical Trials.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for treatment of type 2 diabetes mellitus; however, there have been concerns that GLP-1RA treatment may be associated with an increased incidence of pancreatitis. This study aimed to evaluate the incidence of pancreatitis in a pooled population of type 2 diabetes trials from the clinical development program of the GLP-1RA exenatide as well as to describe patient-level data for all reported cases. METHODS: The primary analysis examined pooled data among patients with type 2 diabetes from the controlled arms of 35 trials (ranging from 4 to 234 weeks' duration) in the integrated clinical databases for exenatide twice daily, once weekly, and once-weekly suspension, excluding comparator arms with other incretin-based therapies. The exposure-adjusted incidence rate (EAIR) of pancreatitis was calculated for exenatide and non-exenatide (non-incretin-based therapy or placebo) treatment groups. Patient-level data were described for all pancreatitis incidences. RESULTS: The primary analysis included 5596 patients who received exenatide and 4462 in the non-exenatide group. The mean duration of study medication exposure for the exenatide and non-exenatide treatment groups was 57.0 and 47.9 weeks, respectively. Pancreatitis was diagnosed in 14 patients (exenatide, n = 8; non-exenatide, n = 6), of whom 13 recovered with or without sequelae. The pancreatitis EAIR was 0.1195 events per 100 patient-years [95% confidence interval (CI), 0.0516-0.2154] in the exenatide group versus 0.1276 events per 100 patient-years (95% CI 0.0468-0.2482) in the non-exenatide treatment group. The EAIR ratio for the exenatide versus non-exenatide treatment group was 0.761 (95% CI 0.231-2.510). CONCLUSION: In this pooled analysis of 10,058 patients among studies comparing exenatide with other glucose-lowering medications or placebo, pancreatitis was rare. The EAIRs of pancreatitis were low and similar between exenatide and non-exenatide treatment groups. No evidence of an association between exenatide and pancreatitis was observed. FUNDING: Bristol-Myers Squibb and AstraZeneca. Plain language summary available for this article.

Glucose Control and Weight Change Associated with Treatment with Exenatide Compared with Basal Insulin: A Retrospective Study.

INTRODUCTION: The aim of the study was to compare glycemic and weight change outcomes for type 2 diabetes patients treated with either exenatide once-weekly (EQW) or exenatide twice-daily (EBID) with those patients treated with basal insulin (BI). METHODS: Retrospective data (2010-2014) were extracted from the Clinical Practice Research Datalink, a UK primary care database. Patients previously naïve to injectable therapy initiating EQW, EBID, or BI were extracted and matched by propensity score within two analyses (EQW vs BI and EBID vs BI). Absolute and relative change in HbA1c and weight from baseline and the proportion of patients achieving HbA1c ≤ 7.0% (53 mmol/mol) combined with weight reduction targets of (1) any weight loss or (2) ≥ 5.0% from baseline were compared at 6 and 12-24 months. RESULTS: A total of 485 patients initiated EQW, 3573 EBID, and 13,503 BI. In the propensity matched EQW versus BI analysis, mean HbA1c decreased with changes of - 1.33% (- 14.5 mmol/mol) and - 1.24% (- 13.5 mmol/mol) at 6 months and - 1.19% (- 13.0 mmol/mol) and - 1.17% (- 12.8 mmol/mol) at 12-24 months, respectively. Respective weight change was - 3.7 kg versus + 1.2 kg (p < 0.001) and - 3.2 kg versus + 2.5 kg (p < 0.001). Significantly more EQW patients achieved the combined HbA1c ≤ 7.0% (53 mmol/mol) and weight loss target (22.4% versus 9.9% at 6 months and 18.2% versus 8.0% at 12-24 months, respectively) and HbA1c ≤ 7.0% (53 mmol/mol) and minimum 5% weight loss (11.8% versus 3.7% at 6 months, and 8.0% versus 0.0% at 12-24 months). For EBID versus BI, similar results were found. CONCLUSION: In this real-world data analysis, exenatide QW and exenatide BID were associated with similar glycemic control and greater weight reduction compared with basal insulin.

Assessment of Saxagliptin Efficacy: Meta-Analysis of 14 Phase 2 and 3 Clinical Trials.

INTRODUCTION: This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens. METHODS: Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164). RESULTS: Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of ß-cell function. CONCLUSION: Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens. FUNDING: AstraZeneca.

Multivariate Prediction Equations for HbA1c Lowering, Weight Change, and Hypoglycemic Events Associated with Insulin Rescue Medication in Type 2 Diabetes Mellitus: Informing Economic Modeling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is chronic and progressive and the cost-effectiveness of new treatment interventions must be established over long time horizons. Given the limited durability of drugs, assumptions regarding downstream rescue medication can drive results. Especially for insulin, for which treatment effects and adverse events are known to depend on patient characteristics, this can be problematic for health economic evaluation involving modeling. OBJECTIVES: To estimate parsimonious multivariate equations of treatment effects and hypoglycemic event risks for use in parameterizing insulin rescue therapy in model-based cost-effectiveness analysis. METHODS: Clinical evidence for insulin use in T2DM was identified in PubMed and from published reviews and meta-analyses. Study and patient characteristics and treatment effects and adverse event rates were extracted and the data used to estimate parsimonious treatment effect and hypoglycemic event risk equations using multivariate regression analysis. RESULTS: Data from 91 studies featuring 171 usable study arms were identified, mostly for premix and basal insulin types. Multivariate prediction equations for glycated hemoglobin A1c lowering and weight change were estimated separately for insulin-naive and insulin-experienced patients. Goodness of fit (R2) for both outcomes were generally good, ranging from 0.44 to 0.84. Multivariate prediction equations for symptomatic, nocturnal, and severe hypoglycemic events were also estimated, though considerable heterogeneity in definitions limits their usefulness. CONCLUSIONS: Parsimonious and robust multivariate prediction equations were estimated for glycated hemoglobin A1c and weight change, separately for insulin-naive and insulin-experienced patients. Using these in economic simulation modeling in T2DM can improve realism and flexibility in modeling insulin rescue medication.

Efficacy and safety of dapagliflozin in Asian patients: A pooled analysis.

BACKGROUND: The efficacy and safety of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has been demonstrated predominantly in Western populations. This study examined the efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes mellitus (T2DM) from eight Phase IIb/III double-blind trials of up to 24 weeks, treated with placebo (n = 497) or dapagliflozin 5 mg (n = 491) or 10 mg (n = 465). METHODS: Efficacy was assessed in the pooled population receiving dapagliflozin 5, 10 mg or placebo over 24 weeks. Safety and tolerability were assessed by collating data for overall adverse events (AEs) and AEs of special interest over the 24-week period. RESULTS: Demographic and baseline characteristics were comparable across treatment groups. Placebo-corrected adjusted mean changes from baseline at 24 weeks in the dapagliflozin 5 and 10 mg groups, respectively, were -0.52% and -0.58% for HbA1c and -1.34 and -1.80 kg for body weight. Modest reductions in blood pressure were also noted with dapagliflozin. Overall, 56.5%, 53.6%, and 58.7% of patients in the placebo and dapagliflozin 5 and 10 mg groups, respectively, experienced AEs, compared with 2.8%, 4.1%, and 2.4% experiencing serious AEs. Genital infections were more frequent with dapagliflozin 10 mg than placebo, whereas the pattern for urinary tract infections was less clear. A transient reduction in mean estimated glomerular filtration rate was noted with dapagliflozin, but was not associated with an increased frequency of serious renal AEs. In contrast, placebo-corrected reductions in urinary albumin : creatinine ratio in patients with albuminuria at baseline suggest a potential renoprotective effect of dapagliflozin. CONCLUSION: Dapagliflozin was efficacious and well tolerated in Asian patients with T2DM.

Treatment Outcomes and Tolerability Following Initiation of GLP-1 Receptor Agonists Among Type 2 Diabetes Patients in Primary Care Practices in Germany.

BACKGROUND: The aim was to investigate real-world treatment outcomes and tolerability of GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes in Germany. METHODS: Patients from 323 primary care practices who started any GLP-1RA therapy (89 Byetta, 108 Bydureon, 347 Victoza patients) between January 1, 2011, and December 31, 2013 (index date) were analyzed retrospectively (Disease Analyzer database, Germany). Changes from baseline in HbA1c, weight, and hypoglycemia were evaluated in 3 follow-up periods of 0-6, 7-12, and 13-18 months. RESULTS: A total of 544 diabetes patients (mean age: 57.9 years; men: 54%) were eligible for the study. Mean (SD) HbA1c (%) decreased from 8.3 (1.4) at baseline to 7.4 (1.2) in 6 months, 7.6 (1.3) in 7-12 months and 7.6 (1.4) in 13-18 months, respectively ( P < .001 for all), while the proportion of patients with HbA1c <7% increased from 15% at baseline to 38%, 36% and 35% in the corresponding periods ( P < .0001 for all). Multivariate-adjusted beta coefficients corresponding to changes in HbA1c (%) from baseline were -.52, -.44, and -.44, respectively, in the follow-up periods for baseline HbA1c (%) ( P < .0001 for all). The prevalence of hypoglycemia at baseline was 0.7%; this did not change significantly after treatment. CONCLUSIONS: In clinical practice, GLP-1RA treatment was associated with improved glycemic control without increased hypoglycemia for up to 18 months. The higher the baseline HbA1c, the greater the HbA1c reduction recorded.

Hypersensitivity Events, Including Potentially Hypersensitivity-Related Skin Events, with Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.

BACKGROUND: In patients with type 2 diabetes mellitus (T2DM), dapagliflozin improves glycemic control and has a safety profile typically related to its mechanism of action. Hypersensitivity adverse events (AEs) have been reported in some patients with sodium-glucose cotransporter 2 (SGLT2) inhibitors, including a recent report of dermatological AEs in Japan. METHODS: We investigated the frequency and characteristics of hypersensitivity AEs, including potentially hypersensitivity-related skin AEs, across 21 phase IIb/III trials of dapagliflozin (N = 5936) versus active or placebo comparators (N = 3403), including the subpopulation of Asian patients (N = 1563). RESULTS: Overall, AEs and serious AEs (SAEs) of hypersensitivity were infrequent and were reported in a similar proportion of patients with dapagliflozin versus active or placebo comparators (AEs: 4.5 vs. 4.3 %; SAEs: 0.2 vs. 0.1 %, respectively). The most common events affected the skin or subcutaneous tissue: rash (dapagliflozin: 1.1 %, comparator: 1.1 %), eczema (0.6, 0.8 %), dermatitis (0.5, 0.4 %), and urticaria (0.5, 0.2 %). Few patients discontinued as a result of hypersensitivity AEs (≤0.2 %). In patients of Asian descent, a lower frequency of hypersensitivity AEs was observed with dapagliflozin versus comparators (2.0 vs. 4.5 %). In the subset of placebo-controlled trials, hypersensitivity AEs were slightly more frequent with dapagliflozin than with placebo across the overall population (4.7 vs. 3.8 %), and less frequent with dapagliflozin in Asian patients (1.5 vs. 5.0 %). CONCLUSIONS: The findings of this post hoc analysis indicate that dapagliflozin does not lead to an increased risk of serious hypersensitivity reactions or potentially hypersensitivity-related skin events among patients with T2DM, including Asian patients. Long-term outcome studies and postmarketing surveillance will provide further information on hypersensitivity reactions with SGLT2 inhibitors. CLINICALTRIALS. GOV IDENTIFIERS: NCT01042977, NCT01031680, NCT00855166, NCT00984867, NCT01294423, NCT00673231, NCT00972244, NCT00680745, NCT00660907, NCT01095653, NCT00831779, NCT00976495, NCT00859898, NCT00736879, NCT00683878, NCT00663260, NCT00643851, NCT00528879, NCT00528372, NCT00357370, NCT00263276.

Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany.

AIM: This study aimed to compare 6-month adherence to therapy with exenatide once weekly (Bydureon(®)) vs liraglutide once daily (Victoza(®)) in patients with type 2 diabetes under primary care in Germany. METHODS: A nationwide longitudinal prescription database (LRx), (between January 2011 and September 2014) was used to analyze adherence to therapy. The proportion of days covered (PDC) by prescription was used as a measure of adherence in the 6-month postindex period. Logistic regression analyses were performed to investigate the associations between glucagon-like peptide-1 receptor agonist therapy adjusting for age, sex, and cotherapy. RESULTS: Therapy was initiated in 5,449 patients with exenatide once weekly (age: 59.7±11.8 years; 51.4% were male) and in 24,648 patients with liraglutide once daily (age: 59.4±11.4 years; 49.7% were male). The median PDC was 0.88 for exenatide once weekly and 0.77 for liraglutide once daily (P<0.05). Once-weekly exenatide was associated with significantly higher adherence. Odds ratio (95% confidence interval) for having a PDC of ≥0.80 was 1.78 (1.62-1.96) for exenatide once weekly compared with liraglutide once daily after adjusting for age, sex, and cotherapy. CONCLUSION: Adherence to treatment with exenatide once weekly was significantly increased compared to that with liraglutide once daily over 6 months in patients with type 2 diabetes.

Osmotic diuresis with SGLT2 inhibition: analysis of events related to volume reduction in dapagliflozin clinical trials.

OBJECTIVE: Dapagliflozin reduces hyperglycemia in type 2 diabetes mellitus (T2DM) and lowers blood pressure, at least in part, secondary to mild diuresis consequent to dapagliflozin-induced glucosuria. While blood-pressure lowering may contribute to cardiovascular risk reduction, dapagliflozin-induced diuresis may potentially contribute to adverse events (AEs) of volume reduction. The present analysis compared the frequency of AEs of volume reduction between dapagliflozin and placebo. METHODS: Pooled data were assessed from 13 placebo-controlled dapagliflozin clinical trials ≤24 weeks in patients with T2DM, overall, and in those at risk (aged ≥65y, estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2), or on antihypertensive therapy). Longer-term (≤104 weeks) data were available for 9 of these trials. RESULTS: The frequency of patients experiencing ≥1 AE of volume reduction over 24 weeks was low overall; 27/2360 (1.1%) with dapagliflozin 10 mg and 17/2295 (0.7%) with placebo; and slightly more frequent in patients ≥65 years (11/665 [1.7%] and 6/711 [0.8%], respectively) and in patients receiving loop diuretics (6/236 [2.5%] and 4/267 [1.5%], respectively). Over 104 weeks, AEs of volume reduction occurred in 38/2026 (1.9%) with dapagliflozin 10 mg and in 27/1956 (1.4%) with placebo; serious AEs of volume reduction in 4/2026 (0.2%) and 6/1956 (0.3%), respectively; and 2 patients in each group discontinued therapy due to these AEs. Dapagliflozin versus placebo incidence rate ratios did not suggest any meaningful increase in frequency of these AEs with dapagliflozin 10 mg, either overall or in those at risk. Although mean eGFR declined by 4.2 ml/min/1.73 m(2) within the first week of dapagliflozin therapy, thereafter eGFR gradually recovered to baseline levels by 104 weeks (mean change from baseline +0.02 mL/min/1.73 m(2); 95%CI: -0.9, 1.0). CONCLUSION: No meaningful increase in frequency of AEs of volume reduction occurred with dapagliflozin 10 mg in patients with T2DM, either overall, or in those at increased risk of these events. However, caution should nevertheless be exercised when prescribing dapagliflozin to elderly patients, those with reduced eGFR, and those receiving antihypertensive medication.

The effect of dapagliflozin on renal function in patients with type 2 diabetes.

BACKGROUND: Dapagliflozin's antihyperglycemic effects are mediated by inhibition of renal sodium-glucose cotransporter-2; therefore, renal safety of dapagliflozin was assessed. METHODS: Twelve double-blind, placebo-controlled, randomized clinical trials were analyzed up to 24 weeks (N = 4545). Six of the 12 studies included long-term data for up to 102 weeks (N = 3036). Patients with type 2 diabetes with normal or mildly impaired renal function [estimated glomerular filtration rate (eGFR) 60 to <90 mL/min/1.73 m(2)] were treated with dapagliflozin (2.5, 5, or 10 mg/day) or placebo. Renal adverse events (AEs) were assessed. RESULTS: Mean eGFR showed small transient reductions with dapagliflozin at week 1, but returned to near baseline values by week 24 and remained stable to week 102. Mean eGFR changes were not very different for dapagliflozin 2.5, 5 and 10 mg versus placebo at 102 weeks: -0.74, 2.52 and 1.38 versus 1.31 mL/min/1.73 m(2), respectively. Renal AEs were similar in frequency to placebo through 24 weeks (1.4, 1.3, 0.9, and 0.9 %, respectively) and 102 weeks (2.4, 1.8, 1.9 and 1.7 %, respectively). Few were serious (0.2, 0.1, 0 and 0.3 %, respectively, over 102 weeks). The most common renal event was serum creatinine increase. In sub-group analyses in patients ≥65 years of age or those with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m(2)), renal AEs occurred more frequently with dapagliflozin than placebo. No events of acute tubular necrosis were reported. CONCLUSION: In patients with normal or mildly impaired renal function, dapagliflozin is not associated with increased risk of acute renal toxicity or deterioration of renal function. All trials included in this analysis are registered at ClinicalTrials.gov: NCT00263276, NCT00972244, NCT00528372, NCT00736879, NCT00528879, NCT00855166, NCT00357370, NCT00680745, NCT00683878, NCT00673231, NCT00643851, NCT00859898.

A Network Meta-analysis Comparing Exenatide Once Weekly with Other GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus.

INTRODUCTION: Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA), approved for treatment of type 2 diabetes mellitus (T2DM). There is limited direct evidence comparing the efficacy and tolerability of exenatide 2 mg once weekly (QW) to other GLP-1 RAs. A network meta-analysis (NMA) was conducted to estimate the relative efficacy and tolerability of exenatide QW versus other GLP-1 RAs for the treatment of adults with T2DM inadequately controlled on metformin monotherapy. METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) that investigated GLP-1 RAs (albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide) at approved doses in the United States/Europe, added on to metformin only and of 24 ± 6 weeks treatment duration. A Bayesian NMA was conducted. RESULTS: Fourteen RCTs were included in the NMA. Exenatide QW obtained a statistically significant reduction in glycated hemoglobin (HbA1c) relative to lixisenatide 20 µg once daily. No other comparisons of exenatide QW to other GLP-1 RAs were statistically significant for change in HbA1c. No statistically significant differences in change in weight, systolic blood pressure, risk of nausea or discontinuation due to adverse events were observed for exenatide QW versus other GLP-1 RAs. CONCLUSION: Exenatide QW demonstrated similar effectiveness and tolerability compared to other GLP-1 RAs, for the treatment of T2DM in adults inadequately controlled on metformin alone.

Effect of the SGLT2 Inhibitor Dapagliflozin on Potassium Levels in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.

INTRODUCTION: Hyperkalemia risk is increased in diabetes, particularly in patients with renal impairment or those receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or potassium-sparing diuretics. Conversely, other diuretics can increase hypokalemia risk. We assessed the effects of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on serum potassium levels in a pooled analysis of clinical trials in patients with type 2 diabetes mellitus (T2DM). METHODS: Fourteen randomized, placebo-controlled, double-blind T2DM studies were analyzed: pooled data from 13 studies of ≤24 weeks' duration (dapagliflozin 10 mg, N = 2360; placebo, N = 2295); and one 52-week moderate renal impairment study in patients with baseline eGFR ≥30 to <60 mL/min/1.73 m(2) (dapagliflozin 10 mg, N = 85; placebo, N = 84). Central laboratory serum potassium levels were determined at each study visit. RESULTS: No clinically relevant mean changes from baseline in serum potassium ≤24 weeks were reported for dapagliflozin 10 mg [-0.05 mmol/L; 95% confidence interval (CI) -0.07, -0.03] versus placebo (-0.02 mmol/L; 95% CI -0.04, 0.00) in the pooled population or in the renal impairment study (-0.03 mmol/L; 95% CI -0.14, 0.08 vs. -0.02 mmol/L; 95% CI -0.13, 0.09, respectively). The incidence rate ratio for serum potassium ≥5.5 mmol/L over 24 weeks for dapagliflozin 10 mg versus placebo was 0.90 (95% CI 0.74, 1.10) in the pooled population; with no increased risk in patients receiving ARBs/ACE inhibitors, or potassium-sparing diuretics, or in those with moderate renal impairment. Slightly more patients receiving dapagliflozin 10 mg had serum potassium ≤3.5 mmol/L versus placebo (5.2% vs. 3.6%); however, no instances of serum potassium ≤2.5 mmol/L were reported. CONCLUSION: Dapagliflozin is not associated with an increased risk of hyperkalemia or severe hypokalemia in patients with T2DM. FUNDING: Bristol-Myers Squibb and AstraZeneca.

Assessing Bladder Cancer Risk in Type 2 Diabetes Clinical Trials: the Dapagliflozin Drug Development Program as a 'Case Study'.

INTRODUCTION: Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, decreases plasma glucose levels by suppressing renal glucose reabsorption and increasing urinary glucose excretion. Previously published pre-clinical data suggest that dapagliflozin lacks carcinogenic potential. This article reviews data on bladder cancer with dapagliflozin to illustrate the challenges in assessing bladder cancer in drug development programs in patients with type 2 diabetes mellitus (T2DM). METHODS: Clinical cases of bladder cancer were analyzed in a pooled population of >9000 patients in 21 phase 2b/3 dapagliflozin clinical trials of up to 208 weeks' duration. RESULTS: In the 21-study pool, demographic and baseline characteristics were generally consistent between dapagliflozin and comparator groups. The overall incidence of malignancies was also balanced between the treatment groups, with an incidence rate ratio (IRR) of 1.035 [95% confidence interval (CI): 0.724, 1.481]. Nine of 5936 dapagliflozin-treated patients and 1 of 3403 comparator-treated patients reported bladder cancer, with an IRR of 5.168 (95% CI: 0.677, 233.55). All of these patients had clinical attributes typical of bladder cancer in the general population (≥60-year-old males; 8 of the 10 patients were current/former smokers). All cases of bladder cancer were reported within 2 years of starting study treatment. There was an absence of detailed workup of hematuria prior to randomization, and no hematuria workup data were collected proactively in the dapagliflozin trials, which is typical of clinical practice. Failure to exclude bladder cancer prior to randomization increases the chance of recruiting patients with pre-existing bladder cancer in clinical trials and may delay the final diagnosis. Of the nine dapagliflozin-treated patients with bladder cancer, eight had microscopic hematuria prior to start of treatment or within 6 months of initiating study treatment. CONCLUSION: The assessment of bladder cancer data illustrates the challenges of characterizing cancer risk in T2DM drug development programs. The totality of evidence to date does not suggest a causal relationship between dapagliflozin and bladder cancer. FUNDING: AstraZeneca.

Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events.

BACKGROUND: Dapagliflozin reduces hyperglycaemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. OBJECTIVES: This study determined the overall safety profile of dapagliflozin in T2DM. METHODS: Safety of dapagliflozin in pooled analyses of phase IIb/III studies was evaluated. Patients received comparator or dapagliflozin as monotherapy, add-on to antidiabetic therapy, or as initial combination with metformin. Proportions of patients with adverse events (AEs) and prespecified parameters related to previous clinical observations and dapagliflozin's action were assessed. The principal analysis used data from 12 placebo-controlled studies. Rare events were assessed across phase IIb/III studies, including special populations, comparator-controlled trials and ongoing long-term extensions. RESULTS: In placebo-controlled studies, hypoglycaemia was more common with dapagliflozin (11.8 %) than placebo (7.0 %), with imbalance driven by add-on of dapagliflozin to sulfonylurea or insulin. Urinary tract infections (4.8 vs 3.7 %), vulvovaginitis/balanitis and related infections (5.1 vs 0.9 %), and non-serious volume-related events (0.8 vs 0.4 %) occurred more often with dapagliflozin than placebo. No substantial AEs were seen on electrolytes or renal function. Pyelonephritis was rare and balanced among treatments; there were no imbalances in fractures or liver test elevations. Overall incidence of malignancies was balanced between groups. The incidence rate ratios of malignancy in certain organ systems were slightly lower for dapagliflozin (renal tract, female reproductive) and in others were slightly lower for control (breast, prostate, bladder). Most AEs associated with dapagliflozin were mild/moderate and related to the mechanism of action. CONCLUSION: Dapagliflozin has a favourable and predictable tolerability profile, with reported events related to its mechanism of action.

Urinary tract infections in patients with diabetes treated with dapagliflozin.

AIMS: Urinary tract infection is common in patients with type 2 diabetes. Possible causative factors include glucosuria, which is a result of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors. Dapagliflozin is an investigative SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes. Data from dapagliflozin multi-trial safety data were analyzed to clarify the association between glucosuria and urinary tract infection. METHODS: Safety data from 12 randomized, placebo-controlled trials were pooled to evaluate the relationship between glucosuria and urinary tract infection in patients with inadequately controlled diabetes (HbA1c >6.5%-12%). Patients were treated with dapagliflozin (2.5, 5, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and events suggestive of urinary tract infection were quantified. RESULTS: This analysis included 3152 patients who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 3.6%, 5.7%, 4.3%, and 3.7%, respectively. Urinary glucose levels, but not the incidence of urinary tract infection, increased progressively with dapagliflozin dosage. Most identified infections were those considered typical for patients with diabetes. Discontinuations due to urinary tract infection were rare: 8 (0.3%) dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient. Most diagnosed infections were mild to moderate and responded to standard antimicrobial treatment. CONCLUSIONS: Treatment of type 2 diabetes with once-daily dapagliflozin 5 or 10mg is accompanied by a slightly increased risk of urinary tract infection. Infections were generally mild to moderate and clinically manageable. This analysis did not demonstrate a definitive dose relationship between glucosuria and urinary tract infection.

Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin.

BACKGROUND: Vulvovaginitis, balanitis, and related genital infections are common in patients with type 2 diabetes. Glucosuria, which is an outcome of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors, is among the possible causes. Dapagliflozin, an SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes, has been studied across a broad spectrum of patients. Analysis of multi-trial safety data may better define the relationship between glucosuria and genital infection. METHODS: Safety data were pooled from 12 randomized, placebo-controlled Phase 2b/3 trials to analyze the association of glucosuria with genital infection in patients with suboptimally controlled diabetes (HbA1c >6.5%-12%). Patients were randomized to receive dapagliflozin (2.5mg, 5mg, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and of events suggestive of genital infection was evaluated. RESULTS: The pooled safety data included 4545 patients: 3152 who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 4.1%, 5.7%, 4.8%, and 0.9%, respectively. Most infections were mild or moderate and responded to standard antimicrobial treatment. Discontinuation due to these events was rare. No clear dose-response relationship between dapagliflozin and genital infection was demonstrated. CONCLUSIONS: Treatment with dapagliflozin 2.5mg, 5mg, or 10mg once daily is accompanied by an increased risk of vulvovaginitis or balanitis, related to the induction of glucosuria. Events were generally mild to moderate, clinically manageable, and rarely led to discontinuation of treatment.

Medical support during the European Union Summit in Gothenburg, Sweden, June 2001.

INTRODUCTION: Several factors are important for the number and severity of medical emergencies during mass-gatherings. The risk of violence, the size and mobility of the crowd, the type of event, weather, and duration of the event all influence the outcome. During the European Union (EU) Summit, from 15-16 June 2001 in Gothenburg, Sweden, approximately 50,000 people participated in 43 protest marches, some which included 15,000 participants. Clashes between police and the protesters occurred. OBJECTIVE: The objective of this study was to analyze the amount and character of injuries as well as the medical complaints in relation to the EU Summit. In addition, the aim of this study was to describe the organization and function of the healthcare services provided during the meeting. METHODS: This study is based on the medical records of patients presenting with injuries and other types of medical emergencies at the healthcare stations during the Summit. RESULTS: In total, 143 patients sought medical care. Fifty-three (37.1%) were police officers. Most patients had minor complaints, but a few were seriously injured. The Patient Presentation Rate (PPR) was 2.7. Nine victims were hospitalized as high priority. CONCLUSION: The PPR for the EU Summit was 2.7, which is in the same range as previously reported from other mass-gatherings.