Association of intercellular adhesion molecule-1 gene with type 1 diabetes

Intercellular adhesion molecule-1 (ICAM-1) functions via its ligands, the leucocyte integrins, in adhesion of immune cells to endothelial cells and in T cell activation. The third immunoglobulin-like extracellular domain binds integrin Mac-1 and contains a common non-conservative aminoacid polymorphism, G241R. Phenotypically, ICAM-1 has been associated with type 1 diabetes, a T-cell-mediated autoimmune disease. We assessed two independent datasets, and noted that R241 was associated with lower risk of type 1 diabetes than is G241 (3695 families, relative risk 0.91, p=0.03; 446 families, 0.60, p=0.006). Our data indicate an aetiological role for ICAM-1 in type 1 diabetes, which needs to be confirmed in future genetic and functional experiments.     

Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus

In the genetic analysis of common, multifactorial diseases, such as type 1 diabetes, true positive irrefutable linkage and association results have been rare to date. Recently, it has been reported that a single nucleotide polymorphism (SNP), 1858C>T, in the gene PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), which has been shown to be a negative regulator of T-cell activation, is associated with an increased risk of type 1 diabetes. Here, we have replicated these findings in 1,388 type 1 diabetic families and in a collection of 1,599 case and 1,718 control subjects, confirming the association of the PTPN22 locus with type 1 diabetes (family-based relative risk (RR) 1.67 [95% CI 1.46-1.91], and case-control odds ratio (OR) 1.78 [95% CI 1.54-2.06]; overall P = 6.02 x 10(-27)). We also report evidence for an association of Trp(620) with another autoimmune disorder, Graves' disease, in 1,734 case and control subjects (P = 6.24 x 10(-4); OR 1.43 [95% CI 1.17-1.76]). Taken together, these results indicate a more general association of the PTPN22 locus with autoimmune disease.     

Prevalence of subacromial-subdeltoid bursitis in shoulder pain: an ultrasonographic study

Purpose

The presence of the subacromial-subdeltoid (SASD) bursa inflammation has recently been proposed as a primary radiologic factor predicting persistent limitation and pain in operated patients. The aim of the study was to verify the hypothesis that pain, or increased shoulder pain, could be associated with SASD bursitis not only in operated patients but also in general population.

Methods

A consecutive series of 1940 shoulder ultrasound examinations were performed by our Department over a 5-year period using linear multi-frequency probes. All reports of examination executed for shoulder pain were reviewed. The video clips were independently reviewed by two radiologists: effusion in the SASD bursa and the presence of other pathological conditions were evaluated and confirmed.

Results

A total of 1147 shoulder video clips were re-evaluated, and 1587 pathologies were detected; 65.5 % of patients had only one pathology, 30.4 % had two and 4.1 % presented three pathologies. The difference between the group with and without effusion is statistically significant for acromioclavicular joint arthritis, supraspinatus tendon calcific tendinopathy, full-thickness and superficial tear of the supraspinatus, traumas and rheumatoid arthritis with a p value <0.01.

Conclusions

Our study shows that the effusion in the SASD bursa is frequently associated with shoulder pain often independently from the underlying pathology; further studies are needed to confirm the statistical significance of this relationship by clarifying possible confounding factors.

Electronic supplementary material

The online version of this article (doi:10.1007/s40477-015-0167-0) contains supplementary material, which is available to authorized users.     

Effect of exenatide QW or placebo,both added to titrated insulin glargine,in uncontrolled type 2 diabetes: The DURATION‐7 randomized study

Aims

To compare the efficacy and safety of adding the glucagon‐like peptide‐1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.

Methods

This multicentre, double‐blind study ( ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8‐week titration phase (glycated haemoglobin [HbA1c] 7.0%‐10.5% [53‐91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2‐hour postprandial glucose, and mean daily IG dose.

Results

Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least‐squares mean difference, ?0.73% [?8.0 mmol/mol]; 95% confidence interval, ?0.93%, ?0.53% [?10.2, ?5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (?1.50 kg; ?2.17, ?0.84; P < .001); and 2‐hour postprandial glucose (?1.52 mmol/L [?27.5 mg/dL]; ?2.15, ?0.90 [?38.7, ?16.2]; P < .001). Significantly more exenatide QW + IG‐treated patients vs placebo + IG‐treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection‐site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.

Conclusions

Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.     

Effects of exenatide once weekly plus dapagliflozin,exenatide once weekly alone,or dapagliflozin alone added to metformin monotherapy in subgroups of patients with type 2 diabetes in the DURATION‐8 randomized controlled trial

This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION‐8 trial. Potential treatment‐by‐subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least‐squares mean reductions ranged from ?8.4 to ?26.1 mmol/mol (?0.77% to ?2.39%) for HbA1c and from ?2.07 to ?4.55 kg for body weight. Potential treatment‐by‐subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m² (least‐squares mean reductions of ?23.6 vs ?19.0 mmol/mol [?2.16% vs ?1.74%], ?17.3 vs ?12.0 mmol/mol [?1.58% vs ?1.10%], and ?17.7 vs ?16.9 mmol/mol [?1.62% vs ?1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment‐by‐subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range ?2.56 to ?3.98 kg vs ?0.56 to ?2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.     

iGlarLixi (insulin glargine 100 U/ml plus lixisenatide) is effective and well tolerated in people with uncontrolled type 2 diabetes regardless of age: A REALI pooled analysis of prospective real-world data

Aim

To evaluate the effectiveness and safety in routine clinical practice of insulin glargine/lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) according to age.

Methods

Patient-level data were pooled from 1316 adults with T2D inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi for 24 weeks. Participants were classified into age subgroups of younger than 65 years (N = 806) and 65 years or older (N = 510).

Results

Compared with participants aged younger than 65 years, those aged 65 years or older had a numerically lower mean body mass index (31.6 vs. 32.6 kg/m²), a longer median diabetes duration (11.0 vs. 8.0 years), were more likely to receive prior basal insulin (48.4% vs. 43.5%) and had a lower mean HbA1c (8.93% [74.10 mmol/mol] vs. 9.22% [77.28 mmol/mol]). Similar and clinically relevant reductions in HbA1c and fasting plasma glucose from baseline to week 24 of iGlarLixi therapy were observed regardless of age. At 24 weeks, least-squares adjusted mean (95% confidence interval [CI]) change in HbA1c from baseline was –1.55% (–1.65% to –1.44%) in those aged 65 years or older and –1.42% (–1.50% to –1.33%) in those aged younger than 65 years (95% CI: –0.26% to 0.00%; P = .058 between subgroups). Low incidences of gastrointestinal adverse events and hypoglycaemic episodes were reported in both age subgroups. iGlarLixi decreased mean body weight from baseline to week 24 in both subgroups (–1.6 kg in those aged ≥ 65 years and –2.0 kg in those aged < 65 years).

Conclusions

iGlarLixi is effective and well tolerated in both younger and older people with uncontrolled T2D.