Diabetes, Obesity and Metabolism Now最新文献

Significant advances have been made in the field of technology to deliver insulin and to continuously monitor glucose levels in patients with type 1 diabetes. Much of these developments have led to the close-loop system (simply known as the artificial pancreas) which simultaneously monitor glucose levels and deliver the optimal amount of insulin in order to achieve a stable glucose levels. A recent study published in the journal Nature Medicine conducted by researchers from the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge looked at the use and efficacy of this system in people with type 2 diabetes. The device used in their study combines an off-the-shelf glucose monitor and insulin pump with an app developed by the team, known as CamAPS HX. This app is run by an algorithm that predicts how much insulin is required to maintain glucose levels in the target range. Previous studies have shown that an artificial pancreas run by a similar algorithm is effective for patients living with type 1 diabetes as well as in patients with type 2 diabetes who require kidney dialysis. Unlike the artificial pancreas used in their previous studies, this new version is a fully closed loop system – i.e. patients do not need to bolus their insulin to adjust for their food.

In this study, 26 patients insulin treated patients with Type 2 diabetes recruited from the primary and secondary care were randomly allocated to a trial of the artificial pancreas for eight weeks and then switch to the standard therapy of multiple daily insulin injections; or to take this standard therapy first and then switch to the artificial pancreas after eight weeks.

They found that patients using the artificial pancreas spent two-thirds (66%) of their time within the target range (between 3.9 and 10.0 mmol/L) compared with 32% in the standard therapy. Furthermore, patients receiving standard therapy experienced 67% of their time with high glucose levels (>10 mmol/L), which was reduced to 33% when using the artificial pancreas. Average glucose levels fell - from 12.6 mmol/L when taking the control therapy to 9.2 mmol/L while using the artificial pancreas. HbA1c level after using the artificial pancreas was 7.3% compared with 8.7% in the standard therapy. Reassuringly, despite tight glucose control, no patients experienced hypoglycaemia during the study. One patient was admitted to hospital while using the artificial pancreas, due to an abscess at the site of the pump cannula. Feedback from participants suggested that participants were happy to have their glucose levels controlled automatically by the system, and nine out of ten (89%) reported spending less time managing their diabetes overall.

While the majority of patients with type 2 diabetes should be and will still be managed by drug therapies, for some patients with type 2 diabetes who requires multiple insulin injection, the use of artificial pancreas technology will improve the

Exercise is an important strategy to improve metabolic outcomes and to reduce risk of developing type 2 diabetes. Previous studies have shown that frequent interruptions of extended sitting with standing or light physical activity reduced triacylglycerol levels – elevated triacylglycerol levels is linked to higher concentrations of fat in the liver, which in turn is strongly associated with insulin resistance. Previous studies have demonstrated that exercise is linked to reduced liver fat and improved insulin sensitivity but the timing of physical activity throughout the day may be a factor in metabolic health. Pre-clinical studies have shown daytime-dependent changes in exercise capacity and metabolic risk markers but few such investigations have been performed in humans.

In a study published in Diabetologia, data from the Netherlands Epidemiology of Obesity (NEO) study, a population-based prospective cohort study was used to investigate processes involved in the development of obesity-related diseases. Study participants had a self-reported body mass index (BMI) of >27 kg/m², aged between 45 and 65 years resulting in a study population of 6,671 individuals. Participants underwent a physical examination during which blood samples were taken to measure fasting and postprandial blood glucose and insulin levels, while demographic, lifestyle and clinical information were obtained via questionnaire. 35% of participants underwent MRI study to have their liver fat content measured. A further random subsample of 955 participants were given a combined accelerometer and heart rate monitor to wear for four consecutive days and nights to monitor movement and activity. Analysis of results obtained from 775 participants for whom complete data sets were available. After adjusting for variables such as age, sex, ethnicity and total body fat, the researchers observed that higher total Physical activity Energy Expenditure (PAEE) were associated with both reduced liver fat content and reduced insulin resistance. An association was also found between insulin resistance and the timing of moderate to vigorous physical activity (MVPA) during the day: performing MVPA in the afternoon or evening was linked to reduced insulin resistance, by 18% and 25% respectively, compared to an even distribution of activity throughout the day, even after adjustment for total amount of MVPA. There was no significant difference in insulin resistance between morning activity and activity spread evenly over the day. These results suggest that timing of physical activity throughout the day is relevant for the beneficial effects of physical activity on insulin sensitivity and should be incorporated into physical activity recommendation. Further studies should assess whether optimal timing of physical activity reduced the occurrence of type 2 diabetes and underlying mechanism for this.

The metabolic benefits of GLP-1 Receptor Agonists and SGLT2 Inhibitors in patients with type 2 diabetes are now well recognised. However, ongoing uncertainties persists regarding their use in people with type 1 diabetes mainly due to safety concerns and lack of evidence from large scale randomised clinical trials. Despite this, Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are often used off-label in the management of type 1 diabetes mellitus (T1DM) in real-world practice as adjuvant therapies to insulin to improve metabolic outcomes. A recent study published in the Journal of Clinical Endocrinology and Metabolism was therefore aimed to determine the efficacy and safety of GLP-1RAs and sodium-glucose SGLT2is in the management of T1DM in real-world practice. Using a retrospective chart review, the investigators identified 104 patients with T1DM who ever used a GLP-1RA (76 patients) or SGLT2i (39 patients) for more than 90 days. They reported that after 1 year of therapy, GLP-1RA users had statistically significant reductions in weight (90.5 kg to 85.4 kg; P < .001), HbA_1c (7.7% to 7.3%; P = .007), and total daily dose of insulin (61.8 units to 41.9 units; P < .001). SGLT2i users also experienced significant reductions in HbA_1c (7.9% to 7.3%; P < .001) and basal insulin (31.3 units to 25.6 units; P = .003). GLP-1RA users compared to SGLT2i users had greater reduction in weight while HbA_1c reduction was comparable between the groups. Importantly, over a mean total duration of use of 29.5 months/patient for both groups, more SGLT2i users experienced diabetic ketoacidosis (DKA) (12.8% vs 3.9%). Discontinuation rate between the two therapies were comparable (26.9% of the time for GLP-1RA users vs 27.7% for SGLT2i users). Overall, this real world study provided evidence of metabolic benefits in patients with type 1 diabetes. However, DKA remains a clinical concern with SGLT2i use, requiring careful patient selection and monitoring, with the risk to benefit ratio of treatment evaluated at an individual level.

Obesity is the excessive growth of adipose tissue resulting from the chronic consumption of excess calories and is a recognised risk factor for developing cardio-metabolic diseases. There is however a significant variation in the size and expandibility of different adipose tissue in humans. The inability of adipose tissue to expand “safely” leads to ectopic fat deposition, causing insulin resistance, type 2 diabetes and cardiovascular conditions – which are more prevalent in men than women. Thus, the mechanisms that control the expandability of adipose tissue are key factors in determining diabetes risk in obesity.

An interesting study from York University have provided new insights on the biological underpinning in gender differences in the risk of developing obesity-related diseases. Previous study from this group has observed that when mice become obese, females grow more new blood vessels to supply the expanding fat tissue with oxygen and nutrients, whereas males grow a lot less. To understand the mechanism regulating this, the team used software to help sift through thousands of genes to zero in on the ones that would be associated with blood vessel growth. They discovered that processes associated with the proliferation of new blood vessels were high in the female mice, whereas the males had a high level of processes associated with inflammation. Thereafter, the investigators examined the behaviour of the endothelial cells ex-vivo. Interestingly, they observed that even when these cells were studied ex-vivo, male and female endothelial cells still behave very differently from each other - female endothelial cells replicated faster, while male endothelial cells displayed greater sensitivity to an inflammatory stimulus. Further studies to investigate the effects of specific genes in humans that regulate endothelial cells growth will provide potential therapeutic target to manage and treat obesity related cardio-metabolic diseases. The study was funded by a grant through the Canadian Institutes of Health Research, as well as the Natural Science and Engineering Research Council of Canada and York's Faculty of Health.

Sodium glucose co-transporter inhibitor (SGLT2i) has emerged not only as a novel therapy to manage hyperglycaemia in people with type 2 diabetes but also shown to confer benefits in reducing a host of cardio-metabolic-renal outcomes. The SGLT2i, Empagliflozin has been shown to reduce cardiovascular death and improve outcomes from heart failure, but its effect in patients with chronic kidney disease (CKD) who are at risk for disease progression are not well understood. A study published in the New England Journal Medicine by the Empa-Kidney Collaborative group was designed to assess the effects of treatment with empaglifozin in a broad range of such patients. The study recruited patients with CKD who had an estimated glomerular filtration rate (eGFR) between 20 and 45 mL/minute/1.73 m² of body-surface area, or who had an eGFR of between 45 and 90 mL/minute/1.73 m² with a urinary albumin-to-creatinine ratio of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 mL per minute per 1.73 m², a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. 6609 patients underwent randomization. During a median of 2.0 years of follow-up, Empagliflozin was associated with a significant 28% reduction in the progression of kidney disease or death from cardiovascular causes. Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was also 14% lower in the empagliflozin group than in the placebo group, but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes or death from any cause. This finding support the wider use of empagliflozin for renal protection in patients irrespective of diabetes status. Reassuringly also, the rates of serious adverse events were similar between empagliflozin and placebo. To optimize clinical safety, clinical implementation of evidence derived from this study require collaborative working between renal and diabetes teams, emphasising the sick day rules for SGLT2i as well as close monitoring of renal and clinical outcomes.

The U.S. Food and Drug Administration (FDA) has recently approved a first-in-class therapy, teplizumab to delay the onset of type 1 diabetes in adults and children aged eight years and older. Teplizumab is an immunotherapy which has been shown to deactivate the immune cells that attack insulin-producing cells, while increasing proportion of cells that help moderate the immune response. Teplizumab is administered by intravenous infusion once daily for 14 consecutive days. This approval adds an important new treatment options for at –risk people to delay clinical diagnosis of type 1 diabetes and may provide people with months to years without the burdens of disease. This may improve clinical outcome given the well recognised association between “life-time disease burden” with risks of long-term vascular complications. The safety and efficacy of Teplizumab were previously evaluated in a randomized, double-blind, event-driven, placebo-controlled trial with 76 people with stage 2 type 1 diabetes. In the trial, participants randomly received teplizumab or a placebo once daily via intravenous infusion for 14 days. The primary measure of efficacy was the time from randomization to development of stage 3 type 1 diabetes diagnosis. The trial showed that over a median follow-up of 51 months, 45% of the 44 people who received teplizumab were later diagnosed with stage 3 type 1 diabetes, compared to 72% of the 32 patients who received a placebo. The mean time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for those who received teplizumab and 25 months for those who received a placebo. This represents a statistically significant delay in the development of stage 3 type 1 diabetes, which would reduce the time to start intensive therapy to manage hyperglycaemia. Crucially, Diabetes UK has suggested that preventative treatments for type 1 diabetes can only be effective when combined with screening programmes to identify those at risk. It is anticipated that this approval will open the door for increased research investment, to develop further effective immunotherapies to prevent the development of type 1 diabetes.

Many patients with Type 2 diabetes will require additional glucose lowering treatment to achieve optimal glucose control. Ensuring treatment adherence is therefore crucial in order to reduce the long-term risks of complications. A study recently published in Nature Medicine, known as the TriMaster study is the first study to evaluate the effectiveness of allowing people with type 2 diabetes to choose their own second/third line medication to manage hyperglycaemia. This approach was thought to balance the potential efficacy with potential side effects profiles of the selected drugs. The study led by academics from the University of Exeter was a randomized double-blind, three-way cross over trial where patients received three different second- or third-line once-daily type 2 diabetes glucose-lowering drugs (pioglitazone 30 mg, sitagliptin 100 mg and canagliflozin 100 mg). As part of a prespecified secondary endpoint, patients' drug preference were examined after they had tried all three drugs. In total, 448 participants were treated with all three drugs which overall showed similar glucose lowering outcomes. In terms of preference, 115 patients (25%) preferred pioglitazone, 158 patients (35%) sitagliptin and 175 patients (38%) canagliflozin. The drug preferred by individual patients was associated with a lower HbA1c (mean: 4.6; 95% CI: 3.9, 5.3) mmol mol⁻¹ lower versus nonpreferred) and was associated with fewer side effects (mean: 0.50; 95% CI: 0.35, 0.64) fewer side effects versus nonpreferred). This study showed that allocating therapy based on patients individually preferred drugs, rather than allocating all patients the overall most preferred drug (canagliflozin), would result in more patients achieving the lowest HbA1c for them (70% versus 30%) and the fewest side effects (67% versus 50%). Given the comparable glucose lowering ability of different drugs, allowing patients to try suitable medications before they choose long-term therapy according to their treatment preference could be a practical alternative to individualised treatment strategy for type 2 diabetes that would facilitate long-term treatment compliance.

A study presented at the American Diabetes Association's (ADA's) 80th Virtual Scientific Sessions – ‘Effect of Dapagliflozin on the Incidence of Diabetes: A Prespecified Exploratory Analysis from DAPA-HF’ has reported that the SGLT2 inhibitor dapagliflozin, when used in patients with heart failure, provided a benefit in preventing type 2 diabetes (T2D).

The original DAPA-HF trial was a phase 3 placebo-controlled international study of dapagliflozin in people with chronic heart failure and a reduced ejection fraction. The trial enrolled 4774 participants with a mean age of 66 years, both with and without type 2 diabetes, that were randomly assigned to take either 10 mg of dapagliflozin or a placebo once daily and were followed for 18.2 months. The study indicated the risk of worsening heart failure or death from cardiovascular causes was lower among the dapagliflozin patients than among those who received the placebo, regardless of the presence or absence of diabetes.

The current planned analysis assessed whether dapagliflozin reduced the incidence of T2D in the 2605 trial participants who did not have T2D when the study began. Of the participants without T2D, 1298 had been assigned to the dapagliflozin group, and 1307 to the placebo group. New-onset T2D was defined as A1C ≥ 6.5% on two consecutive study visits throughout the median 18.2-month follow-up.

The study showed that a total of 157 participants developed T2D, 150 of whom had prediabetes (A1C 5.7-6.4%) at the beginning of the study. Those who developed diabetes had higher mean HbA1c, greater body mass index (BMI) and lower eGFR at the beginning of the study than those who did not develop diabetes. Cox proportional hazards model data showed dapagliflozin reduced new-onset diabetes by 32%, with 4.9% of dapagliflozin patients (64 of 1298) developing T2D, compared to 7.1% (93 of 1307) in the placebo group. In an additional exploratory analysis, those patients who did develop diabetes during the trial experienced a 70% increase in mortality, after adjustments for baseline features.

To put into context – the risk reduction in developing diabetes here is comparable to the 31% reduction with metformin, as seen in the Diabetes Prevention Program. Further studies are needed to see if this observation can be extended to patients without heart failure and reduced ejection fraction, and to evaluate how durable the benefit might be or if the benefit persists after the discontinuation of therapy. It is also tempting to speculate that improvement in cardiac function among people with heart failure may precipitate improvement in glucose metabolism and insulin sensitivity by a variety of mechanism, including via improvement in muscle microvascular blood flow.

Data from a recent renal outcomes trial presented at the ESC Congress showed dapagliflozin significantly prolongs survival in patients with chronic kidney disease with and without type-2 diabetes.

The SGLT2 inhibitor, Ertugliflozin was shown to be non-inferior to placebo for reducing cardiovascular events but significantly reduce heart failure hospitalization, according to a trial presented at the American Diabetes Association's 80th Conference.