Does Gender Influence the Effectiveness and Safety of Insulin Glargine 300 U/ml in Patients with Uncontrolled Type 2 Diabetes? Results from the REALI European Pooled Analysis.

INTRODUCTION: Gender differences in risk factors and treatment outcomes for type 2 diabetes mellitus (T2DM) may exist. We used the REALI European database to investigate whether there were gender-specific differences in baseline characteristics and clinical outcomes among patients with inadequately controlled T2DM initiated on insulin glargine 300 U/ml (Gla-300). METHODS: Data were pooled from 14 multicentre, prospective, interventional and non-interventional studies. Impact of gender on glycaemic control, insulin dose, body weight and hypoglycaemia was evaluated after 12 and 24 weeks of Gla-300 treatment. RESULTS: Women (N = 3857) were older than men (N = 4376) (median age, 65.0 versus 63.0 years), with greater mean body mass index (32.5 versus 31.6 kg/m2) and lower median estimated glomerular filtration rate (77.5 versus 84.0 ml/min/1.73 m2). Peripheral arterial disease and a history of myocardial infarction were more frequent in men (20.1% versus 11.7% and 12.0% versus 5.8%, respectively). At baseline, mean haemoglobin A1c (HbA1c) was 8.74% in men and 8.79% in women. Least square (LS) mean (95% CI) reduction in HbA1c from baseline to week 24 was - 1.17% (- 1.21 to - 1.13) in men and - 1.07% (- 1.11 to - 1.02) in women, resulting in a LS mean difference of - 0.10% (- 0.15 to - 0.05; p < 0.0001). At 24 weeks, 21.6% of women and 27.2% of men achieved target HbA1c of < 7.0% (p < 0.001; chi-square). Reported incidence for symptomatic (8.5% versus 8.7%) and severe (0.3% versus 0.5%) any-time-of-the-day or symptomatic (2.4% versus 1.8%) and severe (0.1% versus 0.2%) nocturnal hypoglycaemia was overall low and comparable between men and women. Changes in daily Gla-300 dose and body weight were also similar. CONCLUSION: Despite some gender differences in baseline characteristics, Gla-300 treatment improved glycaemic control, with overall low hypoglycaemia incidences in both men and women. However, women had statistically significantly lower HbA1c reductions than men, although these differences were clinically modest.

Impact of Age on the Effectiveness and Safety of Insulin Glargine 300 U/mL: Results from the REALI European Pooled Data Analysis.

INTRODUCTION: Patients aged ≥ 65 years continue to be underrepresented in clinical studies related to type 2 diabetes mellitus (T2DM). Accordingly, the REALI pooled analysis was performed to evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) across different age subgroups, using data from 14 interventional and non-interventional studies. METHODS: Pooled efficacy and safety data were collected from 8106 European patients with uncontrolled T2DM who were initiated on or switched to Gla-300 injected once daily for 24 weeks. Patients were categorised into five age subgroups: < 50 (N = 727), 50-59 (N = 2030), 60-69 (N = 3054), 70-79 (N = 1847) and ≥ 80 years (N = 448). RESULTS: Mean baseline haemoglobin A1c (HbA1c) decreased linearly from the youngest (9.10%) to the oldest (8.46%) age subgroup. Following Gla-300 initiation, there were similar HbA1c reductions across age groups, with a least squares mean (95% confidence interval) change in HbA1c from baseline to week 24 of - 1.09% (- 1.18 to - 1.00), - 1.08% (- 1.14 to - 1.03), - 1.12% (- 1.17 to - 1.07), - 1.18% (- 1.24 to - 1.12) and - 1.11% (- 1.23 to - 0.99) in the < 50, 50-59, 60-69, 70-79 and ≥ 80 years subgroups, respectively. The incidences and event rates of reported hypoglycaemia were overall low. Compared to younger age subgroups, lower incidences of symptomatic hypoglycaemia occurring at any time of the day (5.9 vs. 7.6-9.4% for the younger subgroups) or during the night (0.5 vs. 1.6-2.5%) were recorded in patients aged ≥ 80 years. By contrast, the highest incidence of severe hypoglycaemia occurring any time of the day was reported in the subgroup aged ≥ 80 years (1.1 vs. 0.1-0.6% for the younger age subgroups). CONCLUSION: Gla-300 initiated in patients with uncontrolled T2DM provides glycaemic improvement with a favourable safety profile across a wide range of ages.

Glycaemic Control with Insulin Glargine 300 U/mL in Individuals with Type 2 Diabetes and Chronic Kidney Disease: A REALI European Pooled Data Analysis.

INTRODUCTION: Management of type 2 diabetes mellitus (T2DM) in patients with chronic kidney disease is complex. Using the REALI European pooled database, we determined the impact of baseline renal function on the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) initiated in adults with inadequately controlled T2DM. METHODS: Data from 1712 patients with available estimated glomerular filtration rate (eGFR) at baseline were pooled from six 24-week prospective studies. Patients who received once-daily subcutaneous injections of Gla-300 were classified into four renal function subgroups, according to baseline eGFR: ≥ 90 (N = 599), 60-89 (N = 786), 45-59 (N = 219), and 15-44 mL/min/1.73 m2 (N = 108). RESULTS: Compared to those with baseline eGFR ≥ 60 mL/min/1.73 m2, patients with lower eGFR values tended to be older, had a longer T2DM duration, and were more likely to present diabetic complications. After 24 weeks of Gla-300 therapy, the least-squares mean (95% confidence interval) decrease in haemoglobin A1c (HbA1c) from baseline (- 1.14% [- 1.28 to - 1.00], - 1.21% [- 1.34 to - 1.08], - 1.19% [- 1.36 to - 1.01], and - 0.99% [- 1.22 to - 0.76]) and the proportion of patients achieving HbA1c < 7.5% (53.3%, 51.3%, 49.5%, and 51.5%) were comparable in the ≥ 90, 60-89, 45-59, and 15-44 mL/min/1.73 m2 subgroups, respectively. Although the incidence of hypoglycaemia was overall low, more patients in the eGFR 15-44 mL/min/1.73 m2 subgroup experienced hypoglycaemia at night or at any time of the day compared with higher eGFR subgroups. There were no notable differences between the renal function subgroups in the changes in Gla-300 daily dose and body weight from baseline to week 24. CONCLUSION: Although an eGFR of 15-44 mL/min/1.73 m2 was associated with a slightly increased risk of hypoglycaemia among patients with inadequately controlled T2DM, Gla-300 provided glycaemic improvement with an overall favourable safety profile regardless of baseline eGFR.

Rationale and methodology for a European pooled analysis of postmarketing interventional and observational studies of insulin glargine 300 U/mL in diabetes: protocol of REALI project.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a common and heterogeneous disease. Using advanced analytic approaches to explore real-world data may identify different disease characteristics, responses to treatment and progression patterns. Insulin glargine 300 units/mL (Gla-300) is a second-generation basal insulin analogue with preserved glucose-lowering efficacy but reduced risk of hypoglycaemia. The purpose of the REALI pooled analysis described in this paper is to advance the understanding of the effectiveness and real-world safety of Gla-300 based on a large European patient database of postmarketing interventional and observational studies. METHODS AND ANALYSIS: In the current round of pooling, REALI will include data from up to 10 000 subjects with diabetes mellitus (mostly T2DM) from 20 European countries. Outcomes of interest include change from baseline to week 24 in haemoglobin A1c, fasting plasma glucose, self-measured plasma glucose, body weight, insulin dose, incidence and rate of any-time-of-the-day and nocturnal hypoglycaemia. The data pool is being investigated using two complementary methodologies: a conventional descriptive, univariate and multivariable prognostic analysis; and a data-mining approach using subgroup discovery to identify phenotypic clusters of patients who are highly associated with the outcome of interest. By mid-2019, deidentified data of 7584 patients were included in the REALI database, with a further expected increase in patient number in 2020 as a result of pooling additional studies. ETHICS AND DISSEMINATION: The proposed study does not involve collection of primary data. Moreover, all individual study protocols were approved by independent local ethics committees, and all study participants provided written informed consent. Furthermore, patient data is deidentified before inclusion in the REALI database. Hence, there is no requirement for ethical approval. Results will be disseminated via peer-reviewed publications and presentations at international congresses as data are analysed.

Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses.

Monocytes can have important effects on the polarization and expansion of lymphocytes and may contribute to shaping primary and memory T-cell responses in humans and mice. However, their precise contribution in terms of cellular subsets and the molecular mechanisms involved remains to be determined. Mouse monocytes originate from a bone marrow progenitor, the macrophage and DC precursor (MDP), which also gives rise to conventional dendritic cells through a separate differentiation pathway. Mouse monocytes may be grouped in different functional subsets. The CD115(+) Gr1(+) 'inflammatory' monocyte subset can give rise not only to immunostimulatory 'TipDCs' in infected mice but also to immunosuppressive 'myeloid-derived suppressor cells' in tumor-bearing mice. CD115(+) Gr1(+) monocytes can also contribute to the renewal of several resident subsets of macrophages and DCs, such as microglia and Langerhans cells, in inflammatory conditions. The CD115(+) Gr1(-) 'resident' monocyte subset patrols blood vessels in the steady state and extravasates during infection with Listeria monocytogenes or in the healing myocardium. CD115(+) Gr1(-) monocytes are responsible for an early and transient inflammatory burst during Lm infection, which may play a role in the recruitment of other effector cells and subsequently differentiate toward 'M2'-like macrophages that may be involved in wound healing. More research will no doubt confirm the existence of more functional subsets, the developmental relationship between mouse subsets as well as the correspondence between mouse subsets and human subsets of monocytes. We will discuss here the potential roles of monocytes in the immune response, the existence of functional subsets and their relationship with other myeloid cells, including dendritic cells.

Clinical grade expansion of CD45RA, CD45RO, and CD62L-positive T-cell lines from HLA-compatible donors: high cytotoxic potential against AML and ALL cells.

OBJECTIVE: Identification of a clinical grade method for the ex vivo generation of donor-derived T cells cytotoxic against both myeloid and lymphoblastic cells still remains elusive. We investigated rapid generation and expansion of donor derived-allogeneic T-cell lines cytotoxic against patient leukemic cells. MATERIALS AND METHODS: Acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) blasts were cultured 5 days in Stem Span, granulocyte macrophage colony-stimulating factor, interleukin-4, and calcium ionophore. All B-precursor ALL (N22) and AML (N13), but not T-cell ALL (N3), differentiated into mature leukemia-derived antigen-presenting cells (LD-APC). All but one LD-APC generated cytotoxic T lymphocyte (CTL) from adult human leukocyte antigen (HLA)-identical (N8) or unrelated donors (N2). RESULTS: Upon in vitro culture, donor-derived CTL acquired a memory T phenotype, showing concomitant high CD45RA, CD45RO, CD62L expression. CD8(+) cells, but not CD4(+) cells, were granzyme, perforine, and interferon-gamma-positive. Pooled CD4(+) and CD8(+) cells were cytotoxic against leukemic blasts (32%, 30:1 E:T ratio), but not against autologous or patient-derived phytohemagglutinin blasts. LD-APC from five ALL patients were used to generate CTL from cord blood. A mixed population of CD4(+) and CD8(+) cells was documented in 54% of wells. T cells acquired classical effector memory phenotype and showed a higher cytotoxicity against leukemia blasts (47%, 1:1 E:T ratio). Adult and cord blood CTL showed a skewing from a complete T-cell receptor repertoire to an oligo-clonal/clonal pattern. CONCLUSIONS: Availability of these cells should allow clinical trials for salvage treatment of leukemia patients relapsing after allogeneic stem cell transplantation.