Evaluation of validity, reliability and ability to detect change for the Hand Eczema Severity Index (HECSI) and evaluation of HECSI-75 and HECSI-90 as within-patient responder definitions.

BACKGROUND: The Hand Eczema Severity Index (HECSI) is a Clinician-Reported Outcome measure of the severity of hand eczema (HE). OBJECTIVES: This study aimed to evaluate the validity, reliability and ability to detect change of the HECSI, and the HECSI-75 and HECSI-90 as responder definitions. METHODS: Analyses were performed using data from a sample of n = 258 patients with Chronic Hand Eczema (CHE) from a Phase 2b, randomised, double-blind, vehicle-controlled trial of delgocitinib cream, pooled across treatment groups. The measurement properties of the HECSI were assessed and the adequacy of the HECSI-75 and HECSI-90 as responder definitions was explored through cross-tabulation. RESULTS: Inter-item correlations provided support for the scoring, whereby items are grouped by areas of the hand. HECSI demonstrated good test-retest reliability with intra-class correlations >0.70. Construct validity was supported by a logical pattern of correlations with concurrent measures and significant differences in HECSI scores across severity groups (p < 0.001). HECSI was responsive with statistically significant improvements over time and with significant differences (p < 0.001) between improved and stable groups. Data provided support for both HECSI-75 and HECSI-90 as within-patient responder definitions. CONCLUSIONS: HECSI has strong validity, reliability and ability to detect change as a measure of CHE severity. HECSI-75 and HECSI-90 are appropriate responder definitions.

Fixed-ratio combination of insulin degludec and liraglutide (IDegLira) improves cardiovascular risk markers in patients with type 2 diabetes uncontrolled on basal insulin.

In this post hoc analysis we investigated the effects of insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus comparators on cardiovascular (CV) risk markers in participants in the DUAL II (vs. insulin degludec), DUAL V (vs. insulin glargine 100 units/mL) and DUAL VII (vs. basal-bolus therapy) trials, grouped by sex, age (<65 years, ≥65 years) and diabetes duration (<10 years, ≥10 years). Treatment contrasts were in favour of IDegLira in many subgroups for changes from baseline in glycated haemoblogin (DUAL II, DUAL V), body weight (all three trials), systolic blood pressure (BP; all three trials), HDL cholesterol (DUAL VII) and LDL cholesterol (DUAL II, DUAL V). Higher heart rates were seen with IDegLira versus comparators (all three trials) plus significantly higher diastolic BP in men (DUAL V). Differences in treatment effect were seen between sexes in waist circumference (DUAL II), systolic BP (DUAL II, DUAL V) and triglycerides (DUAL VII), and between diabetes durations in LDL cholesterol (DUAL V). In conclusion, IDegLira is associated with a general improvement in CV risk markers compared with basal insulin or basal-bolus therapy after 26 weeks of treatment.

DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality.

AIMS/HYPOTHESIS: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. RESULTS: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. CONCLUSIONS/INTERPRETATION: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529.

Rates of hypoglycaemia are lower in patients treated with insulin degludec/liraglutide (IDegLira) than with IDeg or insulin glargine, regardless of the hypoglycaemia definition used.

AIMS: To re-analyse, using a series of alternative hypoglycaemia definitions, the data from 2 trials, DUAL I and V, in which the once-daily, fixed ratio combination of insulin degludec/liraglutide (IDegLira) was compared with basal insulin therapy. MATERIAL AND METHODS: Post hoc analyses of the DUAL I (patients uncontrolled on oral antidiabetic drugs) and DUAL V (patients uncontrolled on insulin glargine (IGlar) U100) trials were carried out using different definitions of hypoglycaemia and according to whether treatments were administered in the morning or afternoon. Rates of hypoglycaemia for the definitions of confirmed and American Diabetes Association (ADA)-documented symptomatic hypoglycaemia were compared according to age, gender and body mass index (BMI). RESULTS: Although hypoglycaemia rates differed according to the alternative hypoglycaemia definitions, rates were consistently lower with IDegLira vs insulin degludec (IDeg) and IGlar U100. Despite glycated haemoglobin concentrations being lower with IDegLira at end of treatment, confirmed and nocturnal-confirmed hypoglycaemia rates were lower for IDegLira vs IDeg and IGlar U100, irrespective of dosing time. The definitions of confirmed and ADA-documented symptomatic hypoglycaemia did not have a significant effect on the treatment difference between IDegLira and IDeg, liraglutide or IGlar U100 when further assessed by baseline age, gender and BMI. CONCLUSIONS: Treatment with IDegLira, vs IDeg and IGlar U100, resulted in lower rates of hypoglycaemia regardless of dosing time and definition of hypoglycaemia used. The choice of hypoglycaemia definition did not influence the results of analyses when stratified by age, sex and BMI.

Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical Trial.

IMPORTANCE: Achieving glycemic control remains a challenge for patients with type 2 diabetes, even with insulin therapy. OBJECTIVE: To assess whether a fixed ratio of insulin degludec/liraglutide was noninferior to continued titration of insulin glargine in patients with uncontrolled type 2 diabetes treated with insulin glargine and metformin. DESIGN, SETTING, AND PARTICIPANTS: Phase 3, multinational, multicenter, 26-week, randomized, open-label, 2-group, treat-to-target trial conducted at 75 centers in 10 countries from September 2013 to November 2014 among 557 patients with uncontrolled diabetes treated with glargine (20-50 U) and metformin (≥1500 mg/d) with glycated hemoglobin (HbA1c) levels of 7% to 10% and a body mass index of 40 or lower. INTERVENTIONS: 1:1 randomization to degludec/liraglutide (n = 278; maximum dose, 50 U of degludec/1.8 mg of liraglutide) or glargine (n = 279; no maximum dose), with twice-weekly titration to a glucose target of 72 to 90 mg/dL. MAIN OUTCOMES AND MEASURES: Primary outcome measure was change in HbA1c level after 26 weeks, with a noninferiority margin of 0.3% (upper bound of 95% CI, <0.3%). If noninferiority of degludec/liraglutide was achieved, secondary end points were tested for statistical superiority and included change in HbA1c level, change in body weight, and rate of confirmed hypoglycemic episodes. RESULTS: Among 557 randomized patients (mean: age, 58.8 years; women, 49.7%), 92.5% of patients completed the trial and provided data at 26 weeks. Baseline HbA1c level was 8.4% for the degludec/liraglutide group and 8.2% for the glargine group. HbA1c level reduction was greater with degludec/liraglutide vs glargine (-1.81% for the degludec/liraglutide group vs -1.13% for the glargine group; estimated treatment difference [ETD], -0.59% [95% CI, -0.74% to -0.45%]), meeting criteria for noninferiority (P < .001), and also meeting criteria for statistical superiority (P < .001). Treatment with degludec/liraglutide was also associated with weight loss compared with weight gain with glargine (-1.4 kg for degludec/liraglutide vs 1.8 kg for glargine; ETD, -3.20 kg [95% CI, -3.77 to -2.64],P < .001) and fewer confirmed hypoglycemic episodes (episodes/patient-year exposure, 2.23 for degludec/liraglutide vs 5.05 for glargine; estimated rate ratio, 0.43 [95% CI, 0.30 to 0.61],P < .001). Overall and serious adverse event rates were similar in the 2 groups, except for more nonserious gastrointestinal adverse events reported with degludec/liraglutide (adverse events, 79 for degludec/liraglutide vs 18 for glargine). CONCLUSIONS AND RELEVANCE: Among patients with uncontrolled type 2 diabetes taking glargine and metformin, treatment with degludec/liraglutide compared with up-titration of glargine resulted in noninferior HbA1c levels, with secondary analyses indicating greater HbA1c level reduction after 26 weeks of treatment. Further studies are needed to assess longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01952145.

The Efficacy of IDegLira (Insulin Degludec/Liraglutide Combination) in Adults with Type 2 Diabetes Inadequately Controlled with a GLP-1 Receptor Agonist and Oral Therapy: DUAL III Randomized Clinical Trial.

INTRODUCTION: The progressive nature of type 2 diabetes necessitates treatment intensification. This often involves intensification with oral antidiabetic drugs (OADs) initially, followed by other agents, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), with the majority of patients eventually requiring insulin therapy. Therefore, this trial aimed to investigate the efficacy of IDegLira (combination of insulin degludec and liraglutide) in controlling glycemia in adults with type 2 diabetes who were inadequately controlled on a GLP-1RA and OADs. METHODS: In this 26-week open-label phase 3b trial, patients on maximum-dose GLP-1RA therapy (liraglutide once daily or exenatide twice daily) with metformin alone or with pioglitazone and/or sulfonylurea were randomized 2:1 to IDegLira once daily (n = 292) or to unchanged GLP-1RA therapy (n = 146), continuing OADs at the pre-trial dose. RESULTS: After 26 weeks, HbA1c reductions were superior with IDegLira versus unchanged GLP-1RA; estimated treatment difference -0.94% (-10.3 mmol/mol), p < 0.001. Mean HbA1c reduced from 7.8% to 6.4% (61.5 to 46.9 mmol/mol) with IDegLira and from 7.7 to 7.4% (60.8 to 57.1 mmol/mol) with unchanged GLP-1RA. With IDegLira, 75% and 63% of patients achieved HbA1c <7% and ≤6.5%, compared with 36% and 23% on unchanged GLP-1RA, respectively. Fasting plasma glucose and 9-point self-monitored blood glucose profiles improved significantly more with IDegLira versus unchanged GLP-1RA. The mean change in weight was +2.0 kg with IDegLira, versus -0.8 kg with unchanged GLP-1RA. Rates of confirmed hypoglycemia were low, but higher with IDegLira versus unchanged GLP-1RA. The safety profile of IDegLira was consistent with previous findings; both treatments were well tolerated and the rate of nausea was low in both groups. IDegLira improved patient-reported outcomes versus unchanged GLP-1RA. CONCLUSIONS: IDegLira provided superior glycemic control versus unchanged GLP-1RA and represents an efficacious intensification approach in patients inadequately controlled on GLP-1RAs. TRIAL REGISTRATION: ClinicalTrials.gov #NCT01676116. FUNDING: Novo Nordisk.

Treatment of seasonal allergic rhinoconjunctivitis with a once-daily SQ-standardized grass allergy immunotherapy tablet.

OBJECTIVES: Specific immunotherapy with the grass allergy immunotherapy tablet (AIT) has been developed as an effective, well tolerated, and convenient treatment for grass pollen induced seasonal allergic rhinoconjunctivitis (ARC). Six phase II/III randomized, placebo-controlled trials with the duration of a single grass pollen season of treatment using the SQ-standardized grass AIT, Grazax (Phleum pratense, 75,000 SQ-T/2,800 BAU, ALK, Denmark), have been published previously. This review compares results from these trials. METHODS: As outcome measures and methods of assessing them were similar across the trials, we have summarized the main efficacy findings (Total Combined Score [TCS], average daily rhinoconjunctivitis symptom and medication scores, percentage of well days, quality of life scores) during a single season of treatment with grass AIT in adults and children with seasonal ARC. RESULTS: The results of the European and North American trials were similar. Compared with the placebo group, who received symptomatic medications only, treatment with grass AIT resulted in fewer rhinoconjunctivitis symptoms, a lower intake of symptomatic medication, better patient self-rated quality of life and a greater percentage of well days during the entire grass pollen season. The data indicate that grass AIT treatment is equally effective in adults and children; the measured effect varies with pollen exposure, but is comparable across regions and continents, with a consistent difference compared with placebo in TCS that was above 20% for all trials. Local adverse events were experienced by the majority of patients. These reactions were generally mild to moderate in severity and transient in duration. Systemic adverse events were rare. CONCLUSIONS: This review confirms SQ-standardized grass AIT as a suitable therapeutic option for seasonal use in patients aged 5 years or older with grass pollen induced ARC.