Diabet. Med. 29, 682–689 (2012)
Aims To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens.
Methods Internet survey of ...1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin‐treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA.
Results One third (33.2%) of patients reported insulin omission/non‐adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non‐adherence and 5.7 days per month of prandial insulin omission/non‐adherence. Patients and providers indicated the same five most common reasons for insulin omission/non‐adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin‐treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives.
Conclusions Glucose control is inadequate among insulin‐treated patients, in part attributable to insulin omission/non‐adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia.
Aim
To examine factors associated with insulin injection omission/non‐adherence on a global basis.
Methods
Telephone survey of 1530 insulin‐treated adults with self‐reported diabetes (110 type 1 and ...1420 type 2) in China, France, Japan, Germany, Spain, Turkey, UK or USA. Participants had a mean age of ∼60 years, ∼15 years duration of diabetes and ∼9 years duration of insulin treatment. Regression analysis assessed the independent associations (p < 0.05) of country, participant characteristics and treatment‐related beliefs/perceptions with number of days in the past month that an insulin injection was missed or not taken as prescribed.
Results
One third (35%) of respondents reported one or more days (mean: ∼3 days) of insulin omission/non‐adherence. Insulin omission/non‐adherence differed widely across countries (range = 20–44%); differences in days of insulin omission/non‐adherence were maintained after adjustment for other risk factors. Most risk factors had similar relationships with insulin omission/non‐adherence across countries (few interactions with country). Insulin omission/non‐adherence was more frequent among respondents who were male, younger, had type 2 diabetes or more frequent hypoglycaemia, were less successful with other treatment tasks, regarded insulin adherence as less important, had more practical/logistical barriers and difficulties with insulin adherence, were concerned that insulin treatment required lifestyle changes or were dissatisfied with the flexibility of injection timing.
Conclusions
The results of this large‐scale study suggest that insulin omission/non‐adherence is common and associated with several modifiable risk factors (including practical barriers, injection difficulties, lifestyle burden and regimen inflexibility). Additional efforts to address these risk factors might reduce the frequency of insulin omission/non‐adherence and lead to improved clinical outcomes.
Aims
To evaluate the efficacy and safety of twice‐daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed‐dose combination.
Methods
In this 16‐week, phase III, randomized, ...double‐blind placebo‐controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1 : 1 : 1 : 1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight.
Results
Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co‐administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (−0.52 vs. −0.30%, p = 0.0106 and −0.65% vs. −0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of <7%. Efficacy outcomes for dapagliflozin twice daily were numerically similar to those for dapagliflozin once daily. Dapagliflozin twice daily was well tolerated.
Conclusions
Dapagliflozin 2.5 or 5 mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone. This study supports the development of a fixed‐dose combination regimen.
Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and ...patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients' physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic‐lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long‐acting insulin analogues with protaminated human insulin. Enhancing insulin self‐association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long‐acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia.
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αβ T- and B-cell-depleted allografts from ...haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαβ and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/μL, >200 CD19+ cells/μL and >200 CD56+ cells/μL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/μL), for CD3+4+ at day +30 (58 vs 11 cells/μL) and for CD56+ at day +14 (622 vs 27 cells/μL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received alpha beta T- and B-cell-depleted ...allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCR alpha beta and anti-CD19 Abs and immunomagnetic microbeads. The gamma delta T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/ mu L, >200 CD19+ cells/ mu L and >200 CD56+ cells/ mu L for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/ mu L), for CD3+4+ at day +30 (58 vs 11 cells/ mu L) and for CD56+ at day +14 (622 vs 27 cells/ mu L). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Functional diversity is an important aspect of biodiversity, but its relationship to species diversity in time and space is poorly understood. Here we compare spatial patterns of functional and ...taxonomic diversity across marine and terrestrial systems to identify commonalities in their respective ecological and evolutionary drivers. We placed species-level ecological traits into comparable multi-dimensional frameworks for two model systems, marine bivalves and terrestrial birds, and used global species-occurrence data to examine the distribution of functional diversity with latitude and longitude. In both systems, tropical faunas show high total functional richness (FR) but low functional evenness (FE) (i.e. the tropics contain a highly skewed distribution of species among functional groups). Functional groups that persist toward the poles become more uniform in species richness, such that FR declines and FE rises with latitude in both systems. Temperate assemblages are more functionally even than tropical assemblages subsampled to temperate levels of species richness, suggesting that high species richness in the tropics reflects a high degree of ecological specialization within a few functional groups and/or factors that favour high recent speciation or reduced extinction rates in those groups.
Abstract Background The alarming prevalence of heart failure with preserved ejection fraction requires quantification of diastolic dysfunction (DDF). Myocardial diastolic velocity E′ implies that age ...is the most important determinant. We tested the hypothesis that age allows for quantification of DDF and assessment of the structural and metabolic determinants in patients with and without type 2 diabetes (D). Methods This prospective, cross-sectional study assessed cardiovascular, metabolic and ultrasound data in 409 consecutive patients (Diabetes Center, Bogenhausen-Munich) between 20 and 90 years without known cardiac disease and either with (n = 204) or without D but with common prevalence of cardiovascular risk factors, including a subgroup of healthy individuals (H, n = 94). Results In H, E′ related to age as: E′norm = − 0.163 ∗ years + 19.69 (R2 = 0.77, p < 0.0001). According to this 1% reduction by annual physiologic aging, DDF was quantitated as E′ − E′norm . Compared to nondiabetics, D patients were older, had greater BMI, lower E′, more cardiovascular risk and greater DDF. In nondiabetics, grading of DDF by E − E′norm correlated with grading by filling pressure E/E′. Determinants of DDF by multivariate analysis included pulse wave velocity, diastolic blood pressure and the triglyceride/HDL ratio (a marker of insulin resistance) in nondiabetics and in D the same risk factors in reverse sequence and heart rate. Neither left atrial size nor left ventricular mass had significant impact. Conclusions The physiological impact of age on myocardial function consists of a 1% annual reduction in E′ and enables precise quantification of diastolic dysfunction thereby unmasking the importance of metabolic risk for DDF.
We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, ...thiotepa, melphalan and OKT-3.
Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1). Patients were considered high risk because of refractory disease (n=18), cytogenetics (n=6), complete remission (≥ 2) (n=9), chemosensitive relapse in partial remission (n=4) or relapse after prior hematopoietic stem cell transplantation (n=15 allogeneic, n=8 autologous, n=1 both). At haploidentical hematopoietic stem cell transplantation, 30 patients were in complete remission and 31 in partial remission. Grafts contained a median of 7.0 × 10(6) (range 3.2-22) CD34(+) cells/kg, 4.2 × 10(4) (range 0.6-44) CD3(+) T cells/kg and 2.7 × 10(7) (range 0.00-37.3) CD56(+) cells/kg.
Engraftment was rapid with a median of 12 days to granulocytes more than 0.5 × 10(9)/L (range 9-50 days) and 11 days to platelets more than 20 × 10(9) (range 7-38 days). Incidence of grade IIIV acute graft-versus-host-disease and chronic graft-versus-host-disease was 46% and 18%, respectively. Non-relapse mortality on Day 100 was 23% and 42% at two years. Cumulative incidence of relapse/progression at two years was 31%. Kaplan-Meier estimated 1-year and 2-year overall survival with median follow up of 869 days (range 181-1932) is 41% and 28%, respectively.
This regimen allows successful haploidentical hematopoietic stem cell transplantation with reduced intensity conditioning in high-risk patients lacking a suitable donor. (clinicaltrials.gov identifier:NCT00202917).
Haploidentical hematopoietic cell transplantation (HHCT) using CD34 selected grafts is complicated by slow engraftment and immune reconstitution. Engraftment and immune reconstitution might be ...improved using CD3/CD19-depleted grafts and reduced intensity conditioning (RIC). We report on 28 patients after HHCT with CD3/CD19-depleted grafts using RIC, which were prospectively evaluated for engraftment and immune reconstitution. Engraftment was rapid with full chimerism reached on day +15 after HHCT. T-cell reconstitution was delayed with a median of 205 CD3+ cells/μl, 70 CD3+CD4+ cells/μl and 66 CD3+ CD8+ cells/μl on day +100, respectively. A skewed T-cell receptor-Vβ repertoire with oligoclonal T-cell expansions to day +100 and normalization after day +200 was observed. B-cell reconstitution was slow with a median of 100 CD19+ CD20+ cells/μl on day +150. Natural killer (NK) cell engraftment was fast reaching normal values on day +20. An increased natural cytotoxicity receptor and NKG2A, but decreased NKG2D and KIR expressions were observed on NK cells until day +100. We observed a positive impact of donor lymphocyte infusions on immune reconstitution. In conclusion, after HHCT, using CD3/CD19-depleted grafts and RIC, T- and B-cell reconstitution is delayed, whereas NK-cell reconstitution occurs early and fast.
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