Kristina Johnsson

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.

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.

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

ABSTRACT 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 m2, 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 m2 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 m2; 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.

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.

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

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).

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.

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.

Exenatide Once Weekly Plus Metformin for the Treatment of Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomised Controlled Trials

Table 1. Relative effect sizes for change of HbA1c, risk of nausea and treatment discontinuation due to AEs, all GLP-1 RA treatments compared to placebo. • In addition to GLP-1 RAs, two sulfonylureas (glibenclamide, glimepiride), two thiazolidinediones (rosiglitazone, pioglitazone) the dipeptidyl peptidase-4 inhibitor sitagliptin and insulin were included to ensure a connected network of comparative trials when direct evidence was not available. Results are presented only for GLP1RAs.