Impact of telemedical management on hospitalization and mortality in heart failure patients with diabetes: a post-hoc subgroup analysis of the TIM-HF2 trial.

BACKGROUND: The TIM-HF2 study demonstrated that remote patient management (RPM) in a well-defined heart failure (HF) population reduced the percentage of days lost due to unplanned cardiovascular hospital admissions or all-cause death during 1-year follow-up (hazard ratio 0.80) and all-cause mortality alone (HR 0.70). Higher rates of hospital admissions and mortality have been reported in HF patients with diabetes compared with HF patients without diabetes. Therefore, in a post-hoc analysis of the TIM-HF2 study, we investigated the efficacy of RPM in HF patients with diabetes. METHODS: TIM-HF2 study was a randomized, controlled, unmasked (concealed randomization), multicentre trial, performed in Germany between August 2013 and May 2018. HF-Patients in NYHA class II/III who had a HF-related hospital admission within the previous 12 months, irrespective of left ventricular ejection fraction, and were randomized to usual care with or without added RPM and followed for 1 year. The primary endpoint was days lost due to unplanned cardiovascular hospitalization or due to death of any cause. This post-hoc analysis included 707 HF patients with diabetes. RESULTS: In HF patients with diabetes, RPM reduced the percentage of days lost due to cardiovascular hospitalization or death compared with usual care (HR 0.66, 95% CI 0.48-0.90), and the rate of all-cause mortality alone (HR 0.52, 95% CI 0.32-0.85). RPM was also associated with an improvement in quality of life (mean difference in change in global score of Minnesota Living with Heart Failure Questionnaire score (MLHFQ): - 3.4, 95% CI - 6.2 to - 0.6). CONCLUSION: These results support the use of RPM in HF patients with diabetes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01878630.

A Systematic Literature Review of Psychological Interventions for Adults with Type 1 Diabetes.

INTRODUCTION: The psychological burden of type 1 diabetes mellitus (T1DM) is considerable. The condition affects the daily lives of adults living with T1DM (ALWT1DM) in many ways. International guidelines highlight the importance of providing psychological support to ALWT1DM to improve health outcomes and well-being. METHODS: We conducted a systematic literature review of randomised controlled trials (RCTs) to identify the evidence on the impact of psychological interventions on glycaemic control and psychological outcomes in ALWT1DM. Literature searches of Medline, Embase, Cochrane Central Register of Controlled Trials, PsycInfo, and the grey literature were performed to identify relevant RCTs, published in English, from 2001 onward. Fourteen RCTs of ten psychological interventions in ALWT1DM were eligible and included in the qualitative synthesis. The studies varied considerably in terms of duration, target population, endpoints, and efficacy. RESULTS: Overall, psychological interventions did not perform significantly better than control treatments in improving glycaemic control, although selected patient groups did report benefits from some psychological intervention types, such as cognitive behavioural therapy. Although most of the psychological interventions produced small, nonsignificant improvements in self-reported patient functioning, some treatments were effective in reducing diabetes distress and improving mental health, even if no impact on glycaemic control was observed. DISCUSSION: Current guidelines for the treatment of T1DM recommend access to psychological services; however, there is a paucity of high-quality evidence from clinical trials on the effectiveness or preferred structure of psychological support. There is a clear need for more rigorous, large-scale, international research to address the efficacy of psychological interventions in ALWT1DM.

One in Seven Insulin-Treated Patients in Developing Countries Reported Poor Persistence with Insulin Therapy: Real World Evidence from the Cross-Sectional International Diabetes Management Practices Study (IDMPS).

INTRODUCTION: Although poor adherence to insulin is widely recognised, periodic discontinuation of insulin may cause more severe hyperglycaemia than poor adherence. We assessed persistence with insulin therapy in patients with type 1 (T1D) or type 2 diabetes (T2D) in developing countries and the reasons for insulin discontinuation. METHODS: The International Diabetes Management Practices Study collected real-world data from developing countries in seven waves between 2005 and 2017. In Wave 7 (2016-2017), we asked adult patients with T1D and insulin-treated T2D to report whether they had ever discontinued insulin, the estimated duration of discontinuation and underlying reasons. RESULTS: Among 8303 patients recruited from 24 countries by 620 physicians, 4596 were insulin-treated (T1D: 2000; T2D: 2596). In patients with T1D, 14.0% (95% CI: 12.5-15.6) reported having self-discontinued insulin for a median duration of 1.0 month (IQR: 0.5, 3.5). The respective figures in patients with T2D were 13.7% (12.4-15.1) and 2.0 months (IQR: 1.0, 6.0). The main reasons for discontinuation were impact on social life (T1D: 41.0%; T2D: 30.5%), cost of medications and test strips (T1D: 34.4%; T2D: 24.5%), fear of hypoglycaemia (T1D: 26.7%; T2D: 28.0%) and lack of support (T1D: 26.4%; T2D: 25.9%). Other factors included age < 40 years, non-university education and short disease duration (T1D: ≤ 1 year; T2D: > 1-≤ 5 years). Patients with T1D who did not perform self-monitoring of blood glucose (SMBG) or self-adjust their insulin dosage, and patients with T1D or T2D without glucose meters were less likely to persist with insulin. Nearly 50% of patients who reported poor persistence had HbA1c > 75 mmol/mol (> 9%) and > 50% of physicians recommended diabetes education programmes to improve treatment persistence. CONCLUSION: In developing countries, poor persistence with insulin is common among insulin-treated patients, supporting calls for urgent actions to ensure easy access to insulin, tools for SMBG and education.

Patterns of Diabetes Care Among People with Type 1 Diabetes During Ramadan: An International Prospective Study (DAR-MENA T1DM).

INTRODUCTION: To describe the characteristics and care of participants with type 1 diabetes during Ramadan in the Middle East and North Africa. METHODS: The DAR-MENA (Diabetes and Ramadan-Middle East and North Africa) study was a prospective, observational study of adults with type 1 and type 2 diabetes who were Muslim and did/did not intend to fast during Ramadan 2016. Baseline data were collected 6 weeks prior to Ramadan, with a follow-up visit 1-2 months after Ramadan. This is the analysis of the population with type 1 diabetes. Measurements included proportion who fasted, reasons for fasting and not fasting, changes in diabetes treatment, hypoglycemic events, and proportion with access to diabetes education. RESULTS: Of 136 participants with type 1 diabetes, 76.9% (100/130) fasted for at least 1 day, 72.3% (94/130) fasted for at least 15 days, and 48.5% (63/130) fasted for 30 days. The majority (63.0%, 63/100) reported personal decision as a reason to fast. Fear of diabetic complications (58.6%, 17/29) and previous complications related to fasting (48.3%, 14/29) were the most common reasons for not fasting. Adjustment of diabetic medication regimen occurred for 84.6% (115/136) of participants, and 72.8% (99/136) changed their treatment dose. The incidence and number of adverse events for confirmed and severe hypoglycemia were similar before and during Ramadan. Almost half of participants had access to diabetes education (45.6%, 62/136). CONCLUSION: The DAR-MENA study showed that despite the risks associated with fasting for people with type 1 diabetes, almost half fasted for the full 30 days of Ramadan with no significant change in hypoglycemia events. Since the current International Diabetes Federation and Diabetes and Ramadan guidelines do not endorse fasting for people with type 1 diabetes, it is important that those who insist on fasting work closely with their healthcare practitioner to avoid any complications.

Glycaemic benefit of iGlarLixi in insulin-naive type 2 diabetes patients with high HbA1c or those with inadequate glycaemic control on two oral antihyperglycaemic drugs in the LixiLan-O randomized trial.

In this post hoc analysis of the randomized controlled LixiLan-O trial in insulin-naive patients with type 2 diabetes mellitus (T2DM) not controlled with metformin, with or without a second oral antihyperglycaemic drug (OAD), the efficacy and safety of the fixed-ratio combination, iGlarLixi (insulin glargine 100 U [iGlar] and lixisenatide [Lixi]), compared to its individual components was assessed in two patient subgroups: group 1) baseline HbA1c ≥9% (n = 134); group 2) inadequate control (HbA1c ≥7.0% and ≤9.0%) despite administration of two OADs at screening (n = 725). Treatment with iGlarLixi resulted in significantly greater reduction in least squares mean HbA1c compared to treatment with iGlar or Lixi alone in both subgroups (group 1: 2.9%, 2.5%, 1.7% and group 2: 1.5%, 1.2%, 0.7%, respectively). Target HbA1c less than 7% was achieved in more than 70% of patients using iGlarLixi in both subgroups, while mitigating the weight gain observed with use of iGlar alone. Rates of hypoglycaemic events were low overall. These results suggest that treatment with iGlarLixi achieves superior glycaemic control compared to treatment with iGlar or Lixi alone in T2DM patients with HbA1c ≥9% or in those inadequately controlled with two OADs.

The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: An international prospective study (DAR-MENA T2DM).

AIMS: We aimed to describe the characteristics and care of participants with diabetes during Ramadan in the Middle East and North Africa (MENA). METHODS: In this prospective, observational study, we analysed the number of fasted days, number of participants fasting, glycemic control, rate of hypoglycemic events, and lifestyle patterns for participants with T2DM during Ramadan 2016. RESULTS: The population included 1749 participants with T2DM. The mean (SD) duration of fasting was 27.7 (5.0) days, and 57.3% of participants fasted for the full duration of Ramadan. Following Ramadan, a significant improvement in HbA1c, FPG, and PPG was observed (p < 0.0001). Confirmed hypoglycemia increased significantly from before to during Ramadan (incidence: 4.9% vs. 10.4%, p < 0.001; adverse events: 0.11 vs. 0.22 events/month/participant, p < 0.001) and was dependent on the treatment regimen. Severe hypoglycemia incidence was 0.2% before versus 0.9% during Ramadan (p = 0.031), whereas adverse events remained comparable (0.01 events/month/participant; p = 0.154). Most participants (97.4%) reported lifestyle changes during Ramadan. CONCLUSIONS: This prospective study is the first to describe the characteristics and care of participants with T2DM during Ramadan in MENA, and can be utilized in the development of evidence-based care to ensure the safety of participants who fast.

An ongoing role of α-calcitonin gene-related peptide as part of a protective network against hypertension, vascular hypertrophy, and oxidative stress.

α-Calcitonin gene-related peptide (αCGRP) is a vasodilator, but there is limited knowledge of its long-term cardiovascular protective influence. We hypothesized that αCGRP protects against the onset and development of angiotensin II-induced hypertension and have identified protective mechanisms at the vascular level. Wild-type and αCGRP knockout mice that have similar baseline blood pressure were investigated in the angiotensin II hypertension model for 14 and 28 days. αCGRP knockout mice exhibited enhanced hypertension and aortic hypertrophy. αCGRP gene expression was increased in dorsal root ganglia and at the conduit and resistance vessel level of wild-type mice at both time points. ßCGRP gene expression was also observed and shown to be linked to plasma levels of CGRP. Mesenteric artery contractile and relaxant responses in vitro and endothelial NO synthase expression were similar in all groups. The aorta exhibited vascular hypertrophy, increased collagen formation, and oxidant stress markers in response to angiotensin II, with highest effects observed in αCGRP knockout mice. Gene and protein expression of endothelial NO synthase was lacking in the aortae after angiotensin II treatment, especially in αCGRP knockout mice. These results demonstrate the ongoing upregulation of αCGRP at the levels of both conduit and resistance vessels in vascular tissue in a model of hypertension and the direct association of this with protection against aortic vascular hypertrophy and fibrosis. This upregulation is maintained at a time when expression of aortic endothelial NO synthase and antioxidant defense genes have subsided, in keeping with the concept that the protective influence of αCGRP in hypertension may have been previously underestimated.

Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease.

Vascular growth factors play an important role in maintaining the structure and integrity of the glomerular filtration barrier. In healthy adult glomeruli, the proendothelial survival factors vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 are constitutively expressed in glomerular podocyte epithelia. We demonstrate that this milieu of vascular growth factors is altered in streptozotocin-induced type 1 diabetic mice, with decreased angiopoietin-1 levels, VEGF-A upregulation, decreased soluble VEGF receptor-1 (VEGFR1), and increased VEGFR2 phosphorylation. This was accompanied by marked albuminuria, nephromegaly, hyperfiltration, glomerular ultrastructural alterations, and aberrant angiogenesis. We subsequently hypothesized that restoration of angiopoietin-1 expression within glomeruli might ameliorate manifestations of early diabetic glomerulopathy. Podocyte-specific inducible repletion of angiopoietin-1 in diabetic mice caused a 70% reduction of albuminuria and prevented diabetes-induced glomerular endothelial cell proliferation; hyperfiltration and renal morphology were unchanged. Furthermore, angiopoietin-1 repletion in diabetic mice increased Tie-2 phosphorylation, elevated soluble VEGFR1, and was paralleled by a decrease in VEGFR2 phosphorylation and increased endothelial nitric oxide synthase Ser(1177) phosphorylation. Diabetes-induced nephrin phosphorylation was also reduced in mice with angiopoietin-1 repletion. In conclusion, targeted angiopoietin-1 therapy shows promise as a renoprotective tool in the early stages of diabetic kidney disease.

Albuminuria is associated with too few glomeruli and too much testosterone.

Normally, the glomerular filtration barrier almost completely excludes circulating albumin from entering the urine. Genetic variation and both pre- and postnatal environmental factors may affect albuminuria in humans. Here we determine whether glomerular gene expression in mouse strains with naturally occurring variations in albuminuria would allow identification of proteins deregulated in relatively 'leaky' glomeruli. Albuminuria increased in female B6 to male B6 to female FVB/N to male FVB/N mice, whereas the number of glomeruli/kidney was the exact opposite. Testosterone administration led to increased albuminuria in female B6 but not female FVB/N mice. A common set of 39 genes, many expressed in podocytes, were significantly differentially expressed in each of the four comparisons: male versus female B6 mice, male versus female FVB/N mice, male FVB/N versus male B6 mice, and female FVB/N versus female B6 mice. The transcripts encoded proteins involved in oxidation/reduction reactions, ion transport, and enzymes involved in detoxification. These proteins may represent novel biomarkers and even therapeutic targets for early kidney and cardiovascular disease.

A role for TRPV1 in influencing the onset of cardiovascular disease in obesity.

Obesity induced by Western diets is associated with type 2 diabetes mellitus and cardiovascular diseases, although underlying mechanisms are unclear. We investigated a murine model of diet-induced obesity to determine the effect of transient potential receptor vanilloid 1 (TRPV1) deletion on hypertension and metabolic syndrome. Wild-type and TRPV1 knockout mice were fed normal or high-fat diet from 3 to 15 weeks. High-fat diet-fed mice from both genotypes became obese, with similar increases in body and adipose tissue weights. High-fat diet-fed TRPV1 knockout mice showed significantly improved handling of glucose compared with high-fat diet-fed wild-type mice. Hypertension, vascular hypertrophy, and altered nociception were observed in high-fat diet-fed wild-type but not high-fat diet-fed TRPV1 knockout mice. Wild-type, but not high-fat diet-fed TRPV1 knockout, mice demonstrated remodeling in terms of aortic vascular hypertrophy and increased heart and kidney weight, although resistance vessel responses were similar in each. Moreover, the wild-type mice had significantly increased plasma levels of leptin, interleukin 10 and interleukin 1ß, whereas samples from TRPV1 knockout mice did not show significant increases. Our results do not support the concept that TRPV1 plays a major role in influencing weight gain. However, we identified a role of TRPV1 in the deleterious effects observed with high-fat feeding in terms of inducing hypertension, impairing thermal nociception sensitivity, and reducing glucose tolerance. The observation of raised levels of adipokines in wild-type but not TRPV1 knockout mice is in keeping with TRPV1 involvement in stimulating the proinflammatory network that is central to obesity-induced hypertension and sensory neuronal dysfunction.

Circulating vascular progenitor cells and central arterial stiffness in polycystic ovary syndrome.

OBJECTIVE: Subjects with Polycystic ovarian syndrome (PCOS) are at increased risk of Type 2 diabetes mellitus (T2DM). The mechanism of this enhanced risk is unclear. Circulating vascular progenitor cells (VPC) are immature bone marrow derived cells capable of differentiating into mature endothelial cells. VPC number/function and central arterial stiffness predict cardio-metabolic disease in at-risk populations. DESIGN: We studied VPC and arterial stiffness measures in non-obese PCOS subjects as compared to age and body mass index (BMI) matched healthy controls in a cross-sectional study. METHODS: Fourteen subjects with PCOS and 12 controls of similar age, BMI (all <30 kg/m(2)) and metabolic profile were studied. VPC number and in vitro function were studied by flow cytometry and tube formation assays respectively. Augmentation index (AIx), a measure of central arterial stiffness, and central (aortic) blood pressures (BP) were measured by applanation tonometry. RESULTS: Subjects with PCOS had a reduced number, mean±SEM, of circulating CD34(+)133(+) VPCs (317.5±51.0 vs. 558.3±101.2, p = 0.03) and impaired in vitro tube formation (completed tube area 1.0±0.06 vs. 1.2±0.05×10(6) µm(2) p = 0.02). PCOS subjects had significantly higher AIx (18.4±1.9% vs. 4.9±2.0%) and this difference remained significant even after adjustments for age, BMI and smoking (p = 0.003) in multivariate analyses. Central systolic and pulse pressure were higher in PCOS subjects but these differences were not statistically significant after adjustment for age. Brachial systolic and pulse pressures were similar. VPC number/function and arterial stiffness or BP measures were not correlated. CONCLUSIONS: Non-obese PCOS is characterized by a reduced VPC number, impaired VPC function and increased central arterial stiffness. These changes in novel vascular risk markers may explain the enhanced risk of T2DM and CVD in PCOS.