OBJECTIVE: We recently reported that after 26 weeks, exenatide once weekly (EQW) resulted in superior A1C reduction, reduced hypoglycemia, and progressive weight loss compared with daily insulin ...glargine (IG) in patients with type 2 diabetes who were taking metformin alone or with sulfonylurea. This 84-week extension study assessed the long-term safety and efficacy of EQW versus IG. RESEARCH DESIGN AND METHODS: This multicenter, open-label, randomized, two-arm, parallel trial assessed change in A1C, proportions of patients achieving A1C <7.0 and ≤6.5%, body weight, incidence of hypoglycemia, and overall safety. RESULTS: Of 415 patients who completed 26 weeks, 390 (194 EQW and 196 IG patients) entered the extension study. At 84 weeks, A1C decreased from baseline (8.3%) by –1.2% for EQW vs. –1.0% for IG (P = 0.029). The proportions of patients who achieved end point A1C targets <7.0 and ≤6.5% were 44.6% for EQW patients vs. 36.8% for IG patients (P = 0.084) and 31.3% for EQW patients vs. 20.2% for IG patients (P = 0.009), respectively. Patients taking EQW lost 2.1 kg of body weight, whereas those taking IG gained 2.4 kg (P < 0.001). Among patients taking metformin plus sulfonylurea, the incidence of minor hypoglycemia was 24% for EQW patients vs. 54% for IG patients (P < 0.001); among patients taking metformin alone, it was 8% for EQW patients vs. 32% for IG patients (P < 0.001). Among adverse events occurring in ≥5% of patients, diarrhea and nausea occurred more frequently (P < 0.05) in the EQW group than in the IG group (12 vs. 6% and 15 vs. 1%, respectively). CONCLUSIONS: After 84 weeks, patients treated with EQW continued to experience better glycemic control with sustained overall weight loss and a lower risk of hypoglycemia than patients treated with IG.
Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the ...reduction in glycated haemoglobin (HbA1c) in response to dulaglutide. Baseline covariates from patients receiving dulaglutide in six phase III studies (n = 2806) were analysed using a gradient‐boosting method to assess their relative influence on the change in HbA1c after 26 weeks of treatment. Influential variables (relative influence >5%) were further evaluated in univariate and multivariable modelling. The gradient‐boosting analysis showed that the top influential baseline factors associated with HbA1c reduction were: HbA1c (48.8%), age (9.1%), fasting serum glucose (FSG; 8.2%), fasting serum insulin (FSI; 6.7%) and estimated glomerular filtration rate (eGFR; 5.4%). Multivariable regression showed that higher baseline HbA1c was the major factor associated with greater HbA1c reduction coefficient estimates: −0.6% (−6.6 mmol/mol); p < 0.0001. Age ≤65 years, lower FSG level, FSI level ≤55 pmol/L and eGFR ≤100 mL/min/1.73 m2 were associated with greater decreases in HbA1c, but the effect was very small coefficient estimates: −0.05% to −0.2% (−0.6 to −2.2 mmol/mol). These data indicate that higher baseline HbA1c, reflecting poor glycaemic status, is the major factor associated with greater reduction in HbA1c in response to dulaglutide treatment.
The adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related ...lipodystrophy.
Current and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre.
26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0 kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age.
Lipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families.
Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can ...repress the vascular renin-angiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ. Approach and Results- We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients' fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPARγ. Angiotensin II-mediated mitogen-activated protein kinase activity increased in patients' fibroblasts, consistent with RAS constitutive activation. Patients' cells also displayed oxidative stress and inflammation. PPARγ activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes.
Two novel FPLD3-linked PPARG mutations are associated with a defective transrepression of cellular RAS leading to cellular dysfunction, which might contribute to the specific FPLD3-linked severe hypertension.
Aims
The primary objective of the TROPHIES observational study is to estimate the duration of treatment on dulaglutide or liraglutide without a significant treatment change by 24 months in patients ...with type 2 diabetes (T2D) initiating their first injectable treatment with these glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs). This manuscript presents 12‐month interim data.
Materials and Methods
TROPHIES is a prospective, non‐comparative, observational study of patients with T2D in Europe, naïve to injectable antihyperglycaemic treatments and initiating dulaglutide or liraglutide. Data on clinical characteristics, GLP‐1 RA persistence and treatment patterns of glucose‐lowering medication were collected at initiation of first injectable therapy and by 12 months.
Results
By 12 months, 1014 dulaglutide and 991 liraglutide patients were eligible across France, Germany and Italy. Both cohorts presented a high probability 95% confidence interval (CI) of GLP‐1 RA persistence dulaglutide, 0.88 (0.86 to 0.90); liraglutide, 0.83 (0.80 to 0.85) and reduction in mean glycated haemoglobin percentage (95% CI) from baseline dulaglutide, −1.18 (−1.27 to −1.08); liraglutide, −1.15 (−1.26 to −1.05) with 48.2% of dulaglutide and 41.2% of liraglutide patients reaching their individualized glycated haemoglobin percentage target set by the physician at baseline. Mean weight (95% CI) change from baseline was −3.2 kg (−3.6 to −2.8) for dulaglutide and −3.4 kg (−3.9 to −3.0) for liraglutide. Slight changes in concomitant medications were observed compared with baseline.
Conclusions
In the real‐world setting, dulaglutide and liraglutide cohorts achieved good persistence with similarly improved glycaemic control that was accompanied by weight loss at 12 months, consistent with previous clinical trial results.
To assess and compare the technical accuracy of portable glucose meters during the last decade.
One-thousand preprandial (pre) and postprandial (post) capillary whole-blood glucose values measured ...with meters owned mainly by diabetic patients were compared with a single laboratory method yearly from 1989 to 1999. A total of 21,950 capillary measurements and their corresponding laboratory reference values were analyzed at our clinic.
The lowest mean absolute difference was found in 1989 (pre: 2 +/- 22 mg/dl, post: 9 +/- 31 mg/dl) (mean +/- SD). The highest mean absolute difference was observed in 1993 (pre: 31 +/- 33 mg/dl) and 1996 (post: 50 +/- 35 mg/dl). The highest mean relative deviation was observed in 1990 (pre: 16.4%) and 1996 (post: 20.6%). The highest percentage of readings that were within a 5% deviation limit were observed in 1998 (pre: 44.5%) and in 1997 (post: 36.7%). Based on blood glucose levels within +/-5 and +/-10% of laboratory values, the technical accuracy of meters was similar for 1989 and 1999 (P = 0.27 and 0.52, respectively). The percentage of pre values in zone A of Clarke's error grid analysis was >90% in 1989, 1997, 1998, and 1999.
The analytical performance of glucose meters decreased between 1990 and 1996 but was restored between 1997 and 1999. Nevertheless, our data suggest that the technical accuracy of glucose meters has not significantly improved during the last decade. Complementary studies taking into account the preanalytical improvements of the recent meters, as well as their calibration method, appear necessary.
Patient-centered education improves glycemic control in subjects with type 1 diabetes (T1D). E-health technologies are widely used to support medical decision-making, patient advising or ...teleconsultations; however, the active participation of a patient is missing. Challenges remain whether e-health education can be effectively incorporated into clinical pathways. The purpose of the study was to examine the effects of e-health education, compared to standard care, on HbA
MATERIAL AND METHODS: We conducted a literature search (EMBASE, MEDLINE, The Cochrane Library and Web of Science) up to February 2018 for randomized controlled trials (RCTs) of Internet-/ mobile application-based educational interventions, with the active involvement of patients, provided in addition to, or substituting usual care in patients with T1D on intensive insulin therapy. The primary outcome was the standardized difference in means (SDM) of HbA
change from baseline between intervention and comparator groups.
Eight RCTs involving 757 subjects were included on 6335 screened citations. After excluding two trials with a high risk of bias from the meta-analysis, the HbA
change from baseline did not significantly differ between intervention and comparator groups (SDM = -0.154, 95% CI: -0.335 to 0.025; P = 0.01, random-effect model). The number of studies is limited with a relatively short duration. Reporting of educational outcomes was not rigorous.
The effect of e-health educational interventions on HbA
in patients with T1D is comparable to the standard care. This review highlights the need for further well-designed RCTs that will investigate the opportunities of incorporating e-health education into clinical pathways.
Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19.
We ...performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation (IMV), death, intensive care unit (ICU) admission and home discharge at day 7 (D7) or day 28 (D28)) in 2380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736).
The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR: 0.66 (0.49-0.88)), death (OR: 0.49 (0.30-0.79)) and ICU admission (OR: 0.57 (0.43-0.77)) at D7 but only with ICU admission (OR: 0.58 (0.43-0.77)) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, C-reactive protein (CRP), aspartate amino transferase (AST) and estimated glomerular filtration rate (eGFR), according to the CKD-EPI formula predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only.
In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.
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