Risk factors associated with early- versus late-onset implantable cardioverter-defibrillator infections

Aims

The infection rates of implantable cardioverter-defibrillators systems (ICDs) are higher than that of permanent pacemaker. Risk factors associated with ICD infection have not been characterized and are the subject of the current investigation.

Methods

All patients who had an ICD implanted at Mayo Clinic Rochester between 1991 and 2008 were retrospectively reviewed. Each case of ICD infection was matched with two non-infected controls. Cases of ICD infection were further stratified by early- (??6 months) versus late-onset (>6 months) infection. Multivariable analysis was performed to identify significant risk factors for ICD infection.

Results

Sixty-eight patients with ICD infection and 136 matched controls met the inclusion criteria. Thirty-five cases presented with early-onset infection and 33 had late-onset device infection. Staphylococcal species were the most common pathogens in both groups of patients. Patients with early-onset infection were more likely to present with generator pocket infection (p?=?0.02). Patients with multiple comorbid conditions (high Charlson index) tended to have longer hospital stay during implantation admission (p?=?0.009). In a multivariable logistic regression model, the presence of epicardial leads (odds ratio (OR)?=?9.7, p?=?0.03) and postoperative complications at the generator pocket (OR?=?27.2, p?<?0.001) were significant risk factors for early-onset ICD infection, whereas longer duration of hospitalization at the time of implantation (2 days versus 1 day: OR?=?33.1, p?<?0.001; ??3 days versus 1 day: OR?=?49.0, p?<?0.001) and chronic obstructive pulmonary disease (OR?=?9.8, p?=?0.02) were associated with late-onset infections.

Conclusions

Our study findings suggest that risk factors associated with early- and late-onset ICD infection are different. While circumstances that may increase the chances of pocket contamination in the perioperative period are more likely to be associated with early-onset ICD infection, overall poor health of the host may increase the likelihood of late-onset ICD infection. These factors should be considered when developing strategies to minimize risk of device infection.     

Risk factors and early signs of pancreatic cancer in diabetes: screening strategy based on diabetes onset age

Background

Diabetes mellitus (DM) has long been recognized as a risk factor for pancreatic cancer (PaC) and recently has attracted attention as a manifestation of PaC. Diabetes is expected to be a clue for the early detection of PaC; however, no effective screening strategy has been established.

Methods

Forty diabetic patients with PaC were identified and compared with 120 diabetic patients without any malignancies. We analyzed risk factors for and early signs of PaC, focusing on the DM-onset age.

Results

As there were peaks at 40–45 years and 60–65 years in the distribution of DM-onset age, we analyzed the clinical characteristics of and risk factors for PaC according to DM-onset age: i.e., early-onset (<55 years) and late-onset (≥55 years). PaC was diagnosed within 2 years of DM onset (new-onset) in 0 % of the patients with early-onset DM, and in 33 % of those with late-onset DM. The mean duration of DM in patients with early-onset DM with PaC was longer than that in the late-onset patients (26 vs. 9 years; P < 0.01). A family history of DM (odds ratio [OR] 3.60) and use of insulin (OR 3.52) were significant risk factors in patients with early-onset DM, while the onset age of DM (OR 1.12) and multiple diabetic patients in the family (OR 6.13) were risk factors in those with late-onset DM. Body weight loss and exacerbation of DM were seen 12 months prior to PaC diagnosis in both groups.

Conclusions

Our study revealed specific risk factors for and similar early signs of PaC in early-onset and late-onset DM. Thus, we could develop a screening strategy, combining these risk factors specific for DM-onset age with early signs of disease.     

Duration of treatment for candidemia and risk for late-onset ocular candidiasis

Purpose

Few reports have been published on the optimal duration of treatment of ocular candidiasis. We have investigated the incidence of late-onset Candida chorioretinitis and endophthalmitis in patients with candidemia who did not initially receive an ophthalmologic examination. The aim was to determine the duration of initial antifungal treatment that may be sufficient to avoid this complication.

Methods

This was a long-term follow-up study of 144 patients with candidemia who survived for at least 60 days after the onset of candidemia. The frequency of early- and late-onset ocular complications due to candida infection and factors associated with ocular candidiasis were investigated.

Results

Fundoscopy was performed on 60 patients, revealing 12 cases of ocular candida infection (20 %). Risk factors were infection with Candida albicans compared to other Candida species (p = 0.021) and surgery due to solid tumor (p = 0.004). Only one case of late-onset ocular candidiasis occurred among the 84 candidemic patients who did not receive an initial ophthalmologic examination. For unknown reasons, this patient had received only 2 days of systemic antifungal treatment initially.

Conclusions

No case of late-onset ocular candidiasis was detected in unexamined patients who received at least 14 days of antifungal treatment. Based on our results, it would appear that the recommended 2 weeks of treatment after the first negative blood culture are sufficient to avoid late-onset complications due to undiscovered Candida chorioretinitis in patients surviving for more than 60 days after the onset of candidemia.     

Short-term progression of cardiometabolic risk factors in relation to age at type 2 diabetes diagnosis: a longitudinal observational study of 100,606 individuals from the Swedish National Diabetes Register

Aims/hypothesis

The reasons underlying a greater association of premature mortality with early-onset type 2 diabetes relative to late-onset disease are unclear. We evaluated the clinical characteristics at type 2 diabetes diagnosis and the broad trajectories in cardiometabolic risk factors over the initial years following diagnosis in relation to age at diagnosis.

Methods

Our cohort consisted of 100,606 individuals with newly diagnosed type 2 diabetes enrolled in the Swedish National Diabetes Register from 2002 to 2012. The average follow-up time was 2.8 years. Analyses were performed using a linear mixed-effects model for continuous risk factors and a mixed generalised linear model with a logistic link function for dichotomous risk factors.

Results

The individuals diagnosed at the youngest age (18–44 years) were more often male and had the highest BMI (mean of 33.4 kg/m²) at diagnosis and during follow-up compared with all other groups (those diagnosed at 45–59 years, 60–74 years and ≥75 years; p?<?0.05), being ~5 kg/m² higher than the oldest group. Although HbA_1c patterns were similar between all age groups, there was a difference of about 5 mmol/mol (0.45%) between the two groups at 8 years post-diagnosis (p?<?0.05). Additionally, individuals diagnosed younger had ~0.7 mmol/l higher triacylglycerol, and ~0.2 mmol/l lower HDL-cholesterol levels at diagnosis relative to the oldest group. Such differences continued for several years post diagnosis. Yet, although more of these younger individuals were receiving oral glucose-lowering agents, other cardioprotective therapies were prescribed less often in this group. Differences in BMI, blood glucose and lipid levels remained with adjustment for potential confounders, including marital status, education and country of birth, and, where relevant, differential treatments by age, and in those with at least 5 years of follow-up.

Conclusions/interpretation

Individuals who develop type 2 diabetes at a younger age are more frequently obese, display a more adverse lipid profile, have higher HbA_1c and a faster deterioration in glycaemic control compared with individuals who develop diabetes later in life. These differences largely remain for several years after diagnosis and support the notion that early-onset type 2 diabetes may be a more pathogenic condition than late-onset disease.

     

Celiac disease presentation in a tertiary referral centre in India: current scenario

Background

Nondiarrheal celiac disease (NDCD) is being increasingly reported but data from India is limited.

Aim

We undertook this study to compare the clinical spectrum of NDCD with that of diarrheal/classical celiac disease (CCD).

Method

This facility-based retrospective observational study included consecutive patients diagnosed with celiac disease (CD) (as per modified ESPGHAN criteria) from October 2009 to August 2011.

Results

A total of 381 patients were diagnosed with CD during the study period. NDCD was present in 192 (51.8 %). NDCD had higher mean age at presentation (5.8?±?2.8 vs. 6.9?±?2.9 years respectively; p?=?0.003) and longer duration of symptoms prior to diagnosis (2.9?±?1.7 years vs. 3.6?±?2.2 years; p?=?0.02) as compared to CCD. In the NDCD group, the most frequent gastrointestinal (GI) symptoms were recurrent abdominal pain [122 (63.5 %)] and abdominal distension [102 (53.1 %)] followed by constipation [48 (25 %)], vomiting [76 (39.6 %)] and recurrent oral ulcers [89 (46.4 %)]. Vomiting and constipation were more frequently seen in NDCD as compared to CCD (p? <?0.001 in both). Commonly enumerated extraintestinal manifestations in NDCD included failure to thrive [109 (56.8 %)], isolated short stature [36 (18.8 %)], persistent anemia [83 (43.2 %)] and hepatomegaly/splenomegaly or both [56 (29.2 %)]. Associated comorbidities included autoimmune thyroiditis [11 (5.7 %)], type 1 diabetes mellitus [8 (4.2 %)], bronchial asthma [23 (11.9 %)], idiopathic pulmonary hemosiderosis [4 (2.1 %)], Down’s syndrome [3 (1.6 %)], alopecia areata [6 (3.1 %)], polyarthritis [2 (1.0 %)], dermatitis herpetiformis [6 (3.1 %)] and chronic liver disease [6 (3.1 %)]. The number of patients with a Marsh score IIIb and above of duodenal biopsy was significantly more in the CCD group (p?<?0.001).

Conclusions

NDCD is not uncommon in India. Long-term follow up is needed to evaluate the impact of the disease and of treatment in these children.     

Late-onset islet autoimmunity in childhood: the Diabetes Autoimmunity Study in the Young (DAISY)

Aims/hypothesis

We sought to assess the frequency, determinants and prognosis for future diabetes in individuals with islet autoimmunity and whether these factors differ depending on the age of onset of islet autoimmunity.

Methods

A prospective cohort (n = 2547) of children from the general population who had a high-risk HLA genotype and children who had a first-degree relative with type 1 diabetes were followed for up to 21 years. Those with the persistent presence of one or more islet autoantibodies were categorised as early-onset (<8 years of age, n = 143, median 3.3 years) or late-onset (≥8 years of age, n = 64, median 11.1 years), and were followed for a median of 7.4 and 4.7 years, respectively. Progression to diabetes was evaluated by Kaplan–Meier analysis with logrank test. Factors associated with progression to diabetes were analysed using the parametric accelerated failure time model.

Results

Children with late-onset islet autoimmunity were more likely to be Hispanic or African-American than non-Hispanic white (p = 0.004), and less likely to be siblings of individuals with type 1 diabetes (p = 0.04). The frequencies of the HLA-DR3/4 genotype and non-HLA gene variants associated with type 1 diabetes did not differ between the two groups. However, age and HLA-DR3/4 were important predictors of rate of progression to both the presence of additional autoantibodies and type 1 diabetes. Late-onset islet autoimmunity was more likely to present with a single islet autoantibody (p = 0.01) and revert to an antibody-negative state (p = 0.01). Progression to diabetes was significantly slower in children with late-onset islet autoimmunity (p < 0.001).

Conclusions/interpretation

A late onset of islet autoimmunity is more common in African-American and Hispanic individuals. About half of those with late-onset islet autoimmunity progress to show multiple islet autoantibodies and develop diabetes in adolescence or early adulthood. Further investigation of environmental determinants of late-onset autoimmunity may lead to an understanding of and ability to prevent adolescent and adult-onset type 1 diabetes.

     

Eosinophilia in infants with food protein-induced enterocolitis syndrome in Japan

Background

Many Japanese infants with food protein-induced enterocolitis syndrome (FPIES) show eosinophilia, which has been thought to be a characteristic of food protein-induced proctocolitis (FPIP).

Effectiveness of enzyme replacement therapy in adults with late-onset Pompe disease: results from the NCS-LSD cohort study

Objectives

To determine the effectiveness of enzyme replacement therapy (ERT) for adults with late-onset Pompe disease.

Design

A longitudinal cohort study including prospective and retrospective clinical outcome data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data.

Participants

Consenting adults (N?=?62) with a diagnosis of late-onset Pompe disease who attended a specialist treatment centre in England. This cohort represented 83 % of all patients in the UK with a confirmed diagnosis of this rare condition. At study entry, all but three patients were receiving ERT (range of treatment duration, 0 to 3.1 years).

Outcome measures

Percent predicted forced vital capacity (%FVC); ventilation dependency; mobility; 6 min walk test (6MWT); muscle strength and body mass index (BMI).

Results

An association was found between time on ERT and significant increases in the distance walked in the 6MWT (p?p?Conclusions These data provide some further evidence of the effectiveness of ERT in adults with late-onset Pompe disease.

Synopsis

The results of this longitudinal cohort study of 62 adults with late-onset Pompe disease, provide further evidence on the effectiveness of ERT in this rare condition.     

Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes

Aims/hypothesis

High birthweight and increased childhood growth are risk factors for type 1 diabetes. Relative birthweight is associated with HLA genotypes that confer a high risk of diabetes. Our aims were to test whether young children prior to clinical onset of type 1 diabetes have increased: (1) birthweight or birth length standard deviation scores (SDS); (2) height development SDS; or (3) BMI SDS during first 18 months of life and whether these parameters are related to HLA genotypes or mid-parental height (MPH).

Methods

Birthweight, birth length, weight and height were obtained from 58 type 1 diabetes children and 155 controls matched for HLA or not in the Diabetes Prediction in Skåne study.

Results

Birth length SDS corrected for MPH was increased in children developing diabetes compared with all (p?p?p?Conclusions/interpretation Birth length SDS was associated with diabetes risk HLA. When corrected for MPH, children developing diabetes were taller at birth than non-HLA- but not taller than HLA-matched controls. Diabetic children had increased MPH-corrected height up to 18 months of age compared with both HLA- and non-HLA-matched controls. High-risk HLA affects prenatal growth, but other factors may explain the increased postnatal linear growth in children developing diabetes.     

Timing of chemotherapy-induced neutropenia is a prognostic factor in patients with metastatic non-small-cell lung cancer: a retrospective analysis in gemcitabine-plus-platinum-treated patients

Purpose

Chemotherapy-induced neutropenia (CIN) has been associated with better therapeutic results in studies of various tumors. Herein, we explored the relationship between timing (onset) of CIN and clinical outcomes of patients with metastatic non-small-cell lung cancer (NSCLC).

Methods

Patients with stage IV NSCLC receiving at least two cycles of first-line doublet chemotherapy (gemcitabine plus platinum) were reviewed retrospectively. Subjects were stratified by onset of CIN into two groups: early-onset (lowest neutrophil count of cycles 1–2 <2.0 × 10⁹/L) and non-early-onset. The non-early-onset group was further subdivided into late-onset (lowest neutrophil count of cycles 3–6 <2.0 × 10⁹/L) and absence of neutropenia.

Results

A total of 123 patients were studied. Significantly better disease control rate, progression-free survival (PFS), and overall survival (OS) were observed in early-onset versus non-early-onset patients. Median PFS of 5.1 and 3.8 months (p = 0.0016) and median OS of 16.7 and 11.2 months (p = 0.0004) were achieved for these groups, respectively. Patient subsets with late-onset and absence of neutropenia showed similarly poor clinical outcomes, with 4.8 and 3.8 months median PFS (p = 0.5067) and 13.0 and 11.2 months median OS (p = 0.6304), respectively.

Conclusions

Timing of CIN is predictive of prognosis in patients with metastatic NSCLC receiving gemcitabine/platinum doublet chemotherapy. Better clinical outcomes were achieved when onset of neutropenia was early versus late or absent altogether. Further research is warranted to determine whether above findings are applicable to other chemotherapeutic regimens.     

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

Aims/hypothesis

The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A⁺ FDRs) of type 1 diabetic patients.

Methods

Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A⁺ FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5–10 min) and second (120–150 min) release phase, and after glucagon injection (150–160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT.

Results

Seven (41%) FDRs developed diabetes 3–63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p?<?0.05) and HVs (p?<?0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3–21 months later. Two of seven FDRs with normal first-phase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp.

Conclusions/interpretation

Clamp-derived functional variables stratify risk of diabetes in IA-2A⁺ FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage.

Trial registration:

ClinicalTrials.gov NCT00654121

Funding:

The insulin trial was financially supported by Novo Nordisk Pharma nv.     

Rectal cancer in young Indians—Are these cancers different compared to their older counterparts?

Background

The incidence of rectal cancer in young Indians is increasing. Recent evidence suggests a probable existence of noncanonical tumorigenesis pathways in early-onset colorectal cancer patients in India. The aim of the study was to evaluate rectal cancer outcomes in patients ≤40 years with those >40 years.

Methods

An analysis of a prospective database of surgically treated rectal cancer patients ≤40 years (group 1) and those >40 years (group 2) over 2 years was performed. Clinicopathological features, perioperative outcomes, and disease-free survival (DFS) were analyzed.

Results

Of the 512 patients with colorectal cancer treated surgically, 237 patients (group 1—57 patients; group 2—180 patients) were diagnosed with nonmetastatic rectal adenocarcinoma. Patients in group 1 were more likely to present with locally advanced (stage III) disease (p?<?0.005) resulting in a higher proportion of them receiving neoadjuvant chemoradiotherapy (NACT-RT). There was no difference in morbidity and mortality between the two groups. Younger patients had a significantly higher median total and positive lymph node yield (p?<?0.003). Patients in group 1 had a significantly lower overall DFS (p?<?0.005). Stage-specific DFS also demonstrated a significantly lower trend in stage III patients in group 1.

Conclusions

Young rectal cancer patients in India tended to present more frequently with locally advanced tumors resulting in a higher proportion being treated with NACT-RT. Stapled rectal anastomoses could be performed safely in young patients even after NACT-RT. The significantly poorer DFS in young Indian patients with stage III disease was a novel finding and merits further investigation into tumor biology.     

Laparoscopic adjustable gastric banding and progression from impaired fasting glucose to diabetes

Aims/hypothesis

Obesity and dysglycaemia are major risk factors for type 2 diabetes. We determined if obese people undergoing laparoscopic adjustable gastric banding (LAGB) had a reduced risk of progressing from impaired fasting glucose (IFG) to diabetes.

Methods

This was a retrospective cohort study of obese people with IFG who underwent LAGB. Weight and diabetes outcomes after a minimum follow-up period of 4 years (mean ± SD 6.1?±?1.7 years) were compared with those of Australian adults with IFG from a population-based study (AusDiab).

Results

We identified 281 LAGB patients with baseline IFG. Their mean ± SD age and BMI were 46?±?9 years and 46?±?9 kg/m², respectively. The diabetes incidence for patients in the lowest, middle and highest weight loss tertile were 19.1, 3.4 and 1.8 cases/1,000 person-years, respectively. The AusDiab cohort had a lower BMI (28?±?5 kg/m²) and a diabetes incidence of 12.5 cases/1,000 person-years. This increased to 20.5 cases/1,000 person-years when analysis was restricted to the 322 obese AusDiab participants, which was higher than the overall rate of 8.2 cases/1,000 person-years seen in the LAGB group (p?=?0.02). Multivariable analysis of the combined LAGB and AusDiab data suggested that LAGB was associated with ～75% lower risk of diabetes (OR 0.24 [95% CI 0.10, 0.57], p?=?0.004).

Conclusions/interpretation

In obese people with IFG, weight loss after LAGB is associated with a substantially reduced risk of progressing to diabetes over ≥4 years. Bariatric surgery may be an effective diabetes prevention strategy in this population.     

Impact of childhood-onset type 1 diabetes on schooling: a population-based register study

Aims/hypothesis

We investigated the impact of type 1 diabetes on educational achievements in compulsory and upper secondary school, as well as potential long-lasting effects.

Methods

Altogether 2,485 individuals with type 1 diabetes, diagnosed at the age of <15 years and born in 1972–1978, were selected from the Swedish Childhood Diabetes Register, which was linked to national population registers including the Swedish Education Register. For each individual, four controls from the general population, matched for year of birth and residence at the time of diagnosis, were selected by Statistics Sweden (n?=?9,940). We analysed the impact of diabetes on final school grades at 16 years (compulsory school) and 19 years (upper secondary school) and on participation in the labour market at 29 years using linear, logistic, ordered logistic and quantile regression analyses, controlling for demographics and socioeconomic background.

Results

Diabetes had a negative effect on mean final grades (scale of 1–5) in compulsory school (?0.07, p?<?0.001) and theoretical programmes in upper secondary school (?0.07, p?=?0.001). Children with early-onset diabetes (0–4 years) suffered a greater disadvantage as a result of the disease (?0.15, p?=?0.001 in compulsory school). The strongest effect was seen in the lowest deciles of the conditional distribution on mean final grades. At age 29, individuals with diabetes were less likely to be gainfully employed (OR 0.82, 95% CI 0.73, 0.91).

Conclusions/interpretation

The small but significant negative effect of type 1 diabetes on schooling could affect opportunities for further education and career development. Attention must be paid in school to the special needs of children with diabetes.     

Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy

Aims/hypothesis

Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy.

Methods

We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35–80 years) from Swedish cohorts from Skåne (n?=?272) and Västerbotten (n?=?100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin–OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA_1c ≥7.0% (≥53 mmol/mol) at follow-up.

Results

The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m²; p?<?0.001) and follow-up (BMI 27.9 vs 30.2 kg/m²; p?<?0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p?<?0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p?<?0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR?=?1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA_1c, BMI at diagnosis, follow-up time and duration of insulin treatment.

Conclusions/interpretation

Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy.     

Canagliflozin,a sodium glucose co-transporter 2 inhibitor,improves model-based indices of beta cell function in patients with type 2 diabetes

Aims/hypothesis

In rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes.

Methods

Data from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin?+?sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin?+?sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide.

Results

In Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min^?1 m^?2 (mmol/l)^?1 with canagliflozin 100 and 300 mg, respectively (p?<?0.002, Study 1), and 16 (8) and 10 (9) pmol min^?1 m^?2 (mmol/l)^?1 (p?<?0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min^?1 m^?2, respectively; p?<?0.05 for both].

Conclusions/interpretation

Treatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies. Trial registration: Clinicaltrials.gov NCT01081834 (Study 1); NCT01106625 (Study 2); NCT01137812 (Study 3)     

Utilization of Primary and Obstetric Care After Medically Complicated Pregnancies: An Analysis of Medical Claims Data

BACKGROUND

Because pregnancy complications, including gestational diabetes mellitus (GDM) and hypertensive disorders in pregnancy, are risk factors for diabetes and cardiovascular disease, post-delivery follow-up is recommended.

OBJECTIVE

To determine predictors of post-delivery primary and obstetric care utilization in women with and without medical complications.

RESEARCH DESIGN

Five-year retrospective cohort study using commercial and Medicaid insurance claims in Maryland.

SUBJECTS

7,741 women with a complicated pregnancy (GDM, hypertensive disorders and pregestational diabetes mellitus [DM]) and 23,599 women with a comparison pregnancy.

MEASURES

We compared primary and postpartum obstetric care utilization rates in the 12 months after delivery between the complicated and comparison pregnancy groups. We conducted multivariate logistic regression to assess the association between pregnancy complications, sociodemographic predictor variables and utilization of care, stratified by insurance type.

RESULTS

Women with a complicated pregnancy were older at delivery (p?<?0.001), with higher rates of cesarean delivery (p?<?0.0001) and preterm labor or delivery (p?<?0.0001). Among women with Medicaid, 56.6 % in the complicated group and 51.7 % in the comparison group attended a primary care visit. Statistically significant predictors of receiving a primary care visit included non-Black race, older age, preeclampsia or DM, and depression. Among women with commercial health insurance, 60.0 % in the complicated group and 49.5 % in the comparison group attended a primary care visit. Pregnancy complication did not predict a primary care visit among women with commercial insurance.

CONCLUSIONS

Women with pregnancy complications were more likely to attend primary care visits post-delivery compared to the comparison group, but overall visit rates were low. Although Medicaid expansion has potential to increase coverage, innovative models for preventive health services after delivery are needed to target women at higher risk for chronic disease development.     

Postprandial microvascular function deteriorates in parallel with gradual worsening of insulin sensitivity and glucose tolerance in men with the metabolic syndrome or type 2 diabetes

Aims/hypothesis

Hyperinsulinaemia-induced whole-body glucose uptake during a euglycaemic–hyperinsulinaemic clamp is partly mediated by increased capillary density. We hypothesised that physiological insulinaemia in response to a mixed meal may also enhance microvascular function, and that this may be impaired in insulin-resistant individuals and patients with type 2 diabetes.

Methods

Twelve men with uncomplicated type 2 diabetes, 13 with metabolic syndrome and 12 age-matched healthy normoglycaemic controls, mean age 57?±?6 years, underwent skin capillary video microscopy before and 60 and 120 min following a standardised mixed meal to measure baseline capillary density (BCD) and capillary density during post-occlusive peak reactive hyperaemia (PRH), also termed capillary recruitment. Oral glucose insulin sensitivity (Matsuda index) and postprandial hyperglycaemia (2 h AUC_glucose) were calculated.

Results

Fasting BCD was similar among groups, but fasting PRH was lowest in diabetes (p?<?0.05). Postprandially, both BCD and PRH increased in all groups (p?<?0.001); however, the meal-related increase in BCD was significantly lower in diabetes and metabolic syndrome vs controls (both p?<?0.05). At all time points, postprandial PRH was lower in both diabetes and metabolic syndrome vs controls (both p?<?0.05). In pooled analysis, postprandial mean PRH correlated with Matsuda index (r?=?0.386, p?=?0.018) and inversely with 2 h AUC_glucose (r?=??0.336, p?=?0.042).

Conclusions/interpretation

Gradual deterioration in meal-related capillary recruitment was paralleled by decreasing insulin sensitivity and postprandial hyperglycaemia, as assessed in healthy normoglycaemic men, men with the metabolic syndrome and those with type 2 diabetes. These findings suggest that in both impaired glucose tolerance and in overt diabetes microvascular dysfunction might contribute to postprandial dysglycaemia.

Trial registration:

ClinicalTrials.gov NCT00721552     

Omega-3 Polyunsaturated Fatty Acids Increase Plasma Adiponectin to Leptin Ratio in Stable Coronary Artery Disease

Background

Growing evidence suggests a cardioprotective role of omega-3 polyunsaturated fatty acids (PUFA). However, the exact mechanisms underlying the effects of omega-3 PUFA in humans have not yet been fully clarified.

Purpose

We sought to evaluate omega-3 PUFA-mediated effects on adipokines in patients with stable coronary artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI).

Methods

We conducted a prospective, double-blind, placebo-controlled, randomized study, in which adiponectin, leptin and resistin were determined at baseline, 3–5 days and 30 days during administration of omega-3 PUFA 1 g/day (n?=?20) or placebo (n?=?28).

Results

As compared to controls administration of omega-3 PUFA resulted in increase of adiponectin by 13.4 % (P?<?0.0001), reduction of leptin by 22 % (P?<?0.0001) and increase of adiponectin to leptin (A/L) ratio by 45.5 % (P?<?0.0001) at 30 days, but not at 3–5 days. Compared with placebo adiponectin was 12.7 % higher (P?=?0.0042), leptin was 16.7 % lower (P?<?0.0001) and A/L ratio was 33.3 % higher (P?<?0.0001) in the omega-3 PUFA group at 30 days. Resistin decreased similarly in both groups after 1 month, without intergroup differences (P?=?0.32). The multivariate model showed that the independent predictors of changes in adiponectin at 1 month (P?<?0.001) were: omega-3 PUFA treatment, baseline platelet count, total cholesterol and those in leptin (P?<?0.0001) were: omega-3 PUFA treatment and waist circumference. Independent predictors of A/L ratio changes (P?<?0.0001) were: assigned treatment, current smoking and hyperlipidemia.

Conclusions

In high risk stable coronary patients after PCI omega-3 PUFA supplementation improves adipokine profile in circulating blood. This might be a novel, favourable mechanism of omega-3 PUFA action.