Findings from new research published in Diabetes, Obesity and Metablismsuggest that people with type 2 diabetes may need to reduce their blood sugar levels sooner after diagnosis than previously thought, to prevent major cardiovascular events such as heart attacks.
The University of Surrey study Surrey suggests that achieving glycaemic control within the first year of diagnosis reduces the incidence of major cardiovascular events. Additionally, the team found that the greater the variation in blood levels 12-months after diagnosis, the more likely a patient was to experience dangerous cardiovascular events.
Dr Martin Whyte, co-author of the study and Reader in Metabolic Medicine at the University of Surrey, said: “The conventional wisdom has been to slowly and steadily treat type 2 diabetes with diet and medicine dose-escalation over years – the period over which it took people to reduce their sugar levels after diagnosis was thought less important for major vascular protection. However, our observational study suggests that getting blood levels under control quickly — within the first 12 months after diagnosis — will significantly help reduce cardiovascular events.”
Type 2 diabetes is a common condition that results in the level of sugar in the blood becoming too high. The condition is linked to obesity or a family history of type 2 diabetes and can increase a person’s risk of getting serious health conditions.
The University of Surrey’s study used Royal College of General Practitioners’ Research and Surveillance Centre database to perform a comprehensive examination of glycaemic control achieved within the first year of diagnosis and subsequent blood sugar level variability with cardiovascular disease incidents.
Compared to those without diabetes, the COVID mortality risk for people with diabetes is almost double, with almost three times the risk of being critically or severely ill, according to a review of research by researchers from the University of Aberdeen.
Specifically, it was found that while diabetes presents a significant risk of severe illness and death with COVID, good glycaemic control in these patients can mitigate this risk.
The researchers reviewed findings from 158 studies, encompassing more than 270 000 participants from around the world to determine COVID’s impact on people with diabetes.
The pooled results showed that people with diabetes were 1.87 times more likely to die with COVID, 1.59 times more likely to be admitted to ICU, 1.44 times more likely to require ventilation, and 2.88 times more likely to be classed as severe or critical, when compared to patients without diabetes.
This is the first time a study has looked at the risks of COVID in patients with diabetes while factoring in the patients’ location and thereby highlighting potential healthcare resources available as well as possible ethnic differences and other societal factors.
Patients in China, Korea and the Middle East were found to be at higher risk of death than those from EU countries or the US. This, they suggested, may be the result of differences in healthcare systems and affordability of healthcare which may explain the finding that maintaining optimal glycaemic control, significantly reduces adverse outcomes in patients with diabetes and COVID.
Stavroula Kastora, who worked on the study explained: “We found that following a COVID infection, the risk of death for patients with diabetes was significantly increased in comparison to patients without diabetes.
“Equally, collective data from studies around the globe suggested that patients with diabetes had a significantly higher risk of requiring an intensive care admission and supplementary oxygen or being admitted in a critical condition in comparison to patients without diabetes.
“However, we found that the studies that reported patient data from the EU or US displayed less extreme differences between the patient groups. Ultimately, we have identified a disparity in COVID outcomes between the eastern and western world. We also show that good glycaemic control may be a protective factor in view of COVID-related deaths.
“In light of the ongoing pandemic, strengthening outpatient diabetes clinics, ensuring consistent follow up of patients with diabetes and optimising their glycaemic control could significantly increase the chances of survival following a COVID infection.”
Women with obesity and overweight, particularly women with high waist circumference, are more susceptible to fractures than those with normal weight, according to new research presented at the European Congress on Obesity (ECO). In men, however, underweight, not overweight, is associated with a greater risk of broken bones.
Obesity has long been thought to help protect against fractures. This is because mechanical loading on bones, which increases with body weight, helps increase bone mineral density, an important determinant of bone strength.
However, recent studies have suggested that the relationship between obesity and fracture risk varies depending on sex, the skeletal site studied and definition of obesity used (body mass index [BMI] vs waist circumference).
To find out more, Dr Anne-Frederique Turcotte, Endocrinology and Nephrology Unit, CHU de Quebec Research Centre, Quebec City, Canada, and colleagues, analysed data from CARTaGENE, a prospective population-based cohort of almost 20 000 individuals aged 40-70 years from Quebec, Canada.
In women, greater waist circumference (WC) was linearly associated with an increased risk of fracture. For each 5cm (two inch) increase in WC, the risk of fracture at any site was 3% higher and the risk of a distal lower limb fracture was 7% higher. The association between WC and ankle fractures was particularly strong.
In women, greater BMI was associated with a greater risk of distal lower limb fractures. Compared with women with a BMI of 25 kg/m², those with a BMI of 27.5-40 kg/m² showed a greater risk of distal lower limb fractures. The increase in risk rose linearly from 5% in those with a BMI of 27.5 kg/m², to 40% in those with a BMI of 40 kg/m².
Women with a BMI of 22.5 kg/m² had a 5% lower risk of distal lower limb fractures than those with a BMI of 25 kg/m².
It isn’t known why obesity is associated with a higher risk of fractures in women. However, most fractures are a result of a fall and falls are more common in people with obesity. The ankle, unlike the hip and thighbone, is not protected by soft tissue, which could make it more prone to breaking during a fall.
Dr Turcotte added: “Waist circumference was more strongly associated with fractures in women than BMI. This may be due to visceral fat – fat that is very metabolically active and stored deep within the abdomen, wrapped around the organs – secreting compounds that adversely affect bone strength.
“We also know that people with obesity take longer to stabilise their body, when they trip, for example. This is particularly pronounced when weight is concentrated at the front of the body, suggesting that individuals with distribution of body fat in the abdominal area may be at higher risk of falling.”
In men, increases in BMI and WC were not significantly associated with fractures. However, men with underweight were at higher risk of distal upper limb fractures than those with normal weight. Men with a BMI ≤17.5 kg/m² were twice as likely to have distal upper limb fracture as men with a BMI of 25 kg/m².
The researchers say a larger number of fractures in men is needed to determine whether this is a true result or whether the pattern for men follows that for women.
The analyses were adjusted for a number of potential confounders: age, menopausal status, ethnicity, marital status, education, income, area of residence, smoking status, alcohol consumption, physical activity level, supplemental calcium and vitamin D intake, history of fracture and comorbidities and medications known to influence fracture risk.
The study authors said: : “Our findings show that the relationship between obesity and fractures is complex and varies by sex. In women, there was a linear relationship between waist circumference and the incidence of fracture at any site and at the distal lower limb, particularly at the ankle.
“Similar results were observed for women with a BMI between 27 and 40 kg/m². In men however, there was no relationship between obesity and the risk of fracture, although a BMI in the underweight range was associated with a higher risk of some fractures.”
Taking the cholesterol-lowering drug fenofibrate had a modest but statistically significant association with reduced risk of vision-threatening diabetic retinopathy (VTDR), according to results of a large study published in JAMA Ophthalmology. In the study, fenofibrate use was associated with an 8% lower risk of progression compared to non-use.
Fenofibrate use had a greater effect on the risk of proliferative diabetic retinopathy, with a 24% decrease in progression (PDR) but did not significantly affect the risk of developing diabetic macular oedema (DME).
The researchers noted that these findings are in line with evidence showing fenofibrate may protect against diabetes-associated breakdown of the blood-retinal barrier, although ophthalmologists rarely use the drug to treat diabetic eye disease.
“Our positive association for progression to PDR coincides with results of previous clinical trials and adds new information with regards to the impact on DME,” the researchers stated.
Protection against progression to PDR “was found without regards to underlying NPDR [nonproliferative diabetic retinopathy] severity level, which is not well coded within the claims database,” the researchers continued. “Understanding this limitation and how the inclusion of NPDR severity levels that may not benefit from fenofibrates would bias our findings to the null means that the positive association seen in our study is actually an underestimate of the true association.”
While fenofibrate’s mechanism of action in diabetic retinopathy is not well understood, “interest in the use of this oral agent has become substantial,” noted Robert N. Frank, MD. author of an accompanying editorial.
“From the point of view of a clinician with a long-time interest in diabetic retinopathy, its causal mechanisms, and its evolving treatments, the possibility that an oral medication originally used for a different disease may be beneficial for the management of diabetic eye disease is exciting,” Dr Frank wrote.
“The evidence that fenofibrate can slow the progression of diabetic retinopathy is growing, but it has not yet become a widely accepted treatment,” he added. “It will be interesting to see how this large population analysis and the results from the ongoing DRCR Retina Network randomised clinical trial will affect clinical practice in the years to come.”
Two clinical trials that evaluated fenofibrate’s effect on diabetic eye disease, the FIELD study and the ACCORD-Eye trial yielded conflicted findings regarding DME, PDR and progression of diabetic retinopathy. Both trials suggested that only patients with mild nonproliferative eye disease were likely to benefit.
To help inform decision-making on fenofibrate in eye disease, researchers drew on a large health insurer database for 150 252 adults who had NPDR-associated lab values from January 2002 through June 2019. The primary outcomes were a new diagnosis of VTDR (composite of PDR or DME) or DME and PDR individually.
The analysis showed 5835 (3.9%) used fenofibrate. During follow-up, 27 325 patients progressed to VTDR, including 4 086 to PDR and 22 750 to DME. While men accounted for a larger proportion of fenofibrate users (61.1% vs 51.0% of nonusers), patients had similar baseline characteristics.
Study limitations included lack of clinical applicability, not accounting for duration of fenofibrate use, and data being drawn from a single database.
In a study on obese mice fed a high-fat diet, receiving prednisone once weekly improved their exercise endurance and strength, and their reduced weight. The study was published in the Journal of Experimental Medicine. A previous study had found that weekly prednisone was helpful in muscular dystrophy.
“These studies were done in mice. However, if these same pathways hold true in humans, then once-weekly prednisone could benefit obesity,” explained senior author Dr Elizabeth McNally.
“Daily prednisone is known to promote obesity and even metabolic syndrome – a disorder with elevated blood lipids and blood sugar and weight gain,” Dr McNally said. “So, these results, in which we intermittently ‘pulse’ the animals with once-weekly prednisone, are strikingly different. Obesity is a major problem, and the idea that once-weekly prednisone could promote nutrient uptake into muscle might be an approach to treating obesity.”
The once-weekly prednisone, a glucocorticoid steroid, promoted nutrient uptake into the muscles. The researchers also found these mice had increased adiponectin levels, an adipocyte-secreted hormone involved in protecting against diabetes and insulin resistance. Mice that were already obese from eating a high-fat diet were also found to benefit after once-weekly prednisone, experiencing increased strength, running capacity and lower blood glucose.
Most knowledge on steroids like prednisone is derived from studies of daily doses of prednisone
“We see a very different outcome when it is taken once a week,” Dr McNally said. “We need to fine tune dosing to figure out the right amount to make this work in humans, but knowing adiponectin might be one marker could provide a hint at determining what the right human dose is.”
Dr McNally described the weekly dose as “a bolus, or spike, of nutrients going into your muscle.”
“We think there is something special about promoting this spike of nutrients into muscle intermittently, and that it may be an efficient way to improve lean body mass,” she added.
“What is exciting to me about this work is the finding that a simple change in the dosing frequency can transform glucocorticoid drugs from inducers to preventers of obesity,” said corresponding author Mattia Quattrocelli. “Chronic once-daily intake of these drugs is known to promote obesity. Here we show that dosing the same type of drug intermittently – in this case, once weekly – reverses this effect, promotes muscle metabolism and energy expenditure, and curtails the metabolic stress induced by a fat-rich diet.”
Many patients take prednisone daily for different immune conditions, which has side effects including weight gain and even muscle atrophy with weakness. Investigators want to determine whether patients can get the same immune benefit with intermittent prednisone dosing, which could be much more beneficial to the muscle.
Dr McNally’s team previously found that intermittent prednisone administration was helpful for muscular dystrophy, showing once weekly prednisone improved strength, recently reporting that a pilot trial in humans with muscular dystrophy in which one weekly dose of prednisone improved lean mass.
McNally wants to identify biomarkers most critical to measure a beneficial response to prednisone.
“If we can determine how to choose the right dose of prednisone that minimises atrophy factors and maximises positive markers like adiponectin, then we can really personalise the dosing of prednisone,” she said.
The group also recently showed that weekly prednisone uses strikingly different molecular pathways to strengthening the muscle in male versus female mice, based on a new study just published in the Journal of Clinical Investigation by Isabella Salamone, a graduate student in Dr McNally’s lab.
The benefits of weekly prednisone are linked to circadian rhythms, according to another new study published in Science Advances. Human cortisol and steroid levels spike early in the morning before awakening.
“If you don’t give the drug at the right time of day, you don’t get the response,” Quattrocelli said. “In mice, we obtained good effects with intermittent prednisone in muscle mass and function when we dose them at the beginning of their daytime. Mice have a circadian rhythm inverted to us, as they generally sleep during the daytime and are active at night. This could mean that the optimal dosing time for humans during the day could be in the late afternoon/early evening, but this needs to be appropriately tested.”
Conducting these studies in mice is a major limitation, Dr McNally said.
“While we are encouraged by the pilot study in humans with muscular dystrophy, mouse muscles have more fast-twitch fibres than humans, and slow-twitch muscle could be different,” Dr McNally said. “More studies are needed to try to better understand whether these same mechanisms work in human muscles.”
Findings from a new show that an experimental ‘gene silencing’ therapy reduced blood levels of lipoprotein(a) by up 98%. This is significant as lipoprotein(a) is a key cardiovascular risk driver which is determined largely by genetics and not modifiable lifestyle factors, and which cannot be lowered by current medical means.
Trial participants receiving higher doses of SLN360 – a small interfering RNA (siRNA) therapeutic that ‘silences’ the gene responsible for lipoprotein(a) production – saw their lipoprotein(a) levels drop by as much as 96%-98%. Five months later, these participants’ lipoprotein(a) – also known as Lp(a) – levels remained 71%-81% lower than baseline.
The findings suggest this siRNA therapy could be a promising treatment to help prevent premature heart disease in people with high levels of Lp(a), which is estimated to affect 64 million people in the United States and 1.4 billion people worldwide.
“These results showed the safety and strong efficacy of this experimental treatment at reducing levels of Lp(a), a common, but previously untreatable, genetically-determined risk factor that leads to premature heart attack, stroke and aortic stenosis,” said the study’s lead author Steven E. Nissen, MD “We hope that further development of this therapy also will be shown to reduce the consequences of Lp(a) in the clinical setting through future studies.”
Lp(a) has similarities to LDL. Lp(a) is made in the liver, where an extra protein called apolipoprotein(a) is attached to an LDL-like particle. Unlike other types of cholesterol particles, Lp(a) levels are 80 to 90% genetically determined. The structure of the Lp(a) particle causes the accumulation of plaques in arteries, which play a significant role in heart disease. Elevated Lp(a) greatly increases the risk of heart attacks and strokes.
Although cardiovascular risk-reduction therapies that lower LDL cholesterol and other lipids exist, there are treatments to lower Lp(a). Since Lp(a) levels are genetically determined, lifestyle changes such as diet or exercise have no effect. In the current study, the siRNA therapy reduces Lp(a) levels by “silencing” the gene responsible for Lp(a) production and blocking creation of apolipoprotein(a) in the liver.
In the APOLLO trial, researchers enrolled 32 participants with Lp(a) levels above 15 nmol/L, with a median level of 224nmol/L (75nmol/L or less is considered normal). Eight participants received a placebo and the remaining received one of four doses of SLN360 via a single subcutaneous injection. The doses were 30mg, 100mg, 300mg and 600mg. Participants were closely observed for the first 24 hours after their injection and then followed up for five months.
Compared to baseline, participants receiving 300mg and 600mg of SLN360 experienced a maximum of 96% and 98% reduction in Lp(a) levels, and a reduction of 71% and 81% at five months. Those receiving a placebo saw no change in Lp(a) levels. The highest doses also reduced LDL cholesterol by about 20%-25%. There were no major safety consequences reported and the most common side effect was temporary soreness at the injection site. The study was extended and researchers will continue to follow participants for a total of one year.
High lipid levels in people with type 2 diabetes and obesity are more harmful than previously thought, according to findings from a new study which found that stressed cells can damage nearby cells.
In patients with metabolic diseases, elevated lipid levels in the blood create stress in muscle cells – a reaction to changes outside the cell which damage their structure and function.
The study, published in Nature Communications, shows that these stressed-out cells give off a signal which can be passed on to other cells.
The signals, known as ceramides, may confer a short-term protective benefit, because they are part of a mechanism designed to reduce stress in the cell. But in long term conditions such as metabolic diseases, the signals can actually kill the cells and worsen symptoms and the illness.
High lipid levels have long been known to damage tissues and organs, contributing to the development of cardiovascular and metabolic diseases including type 2 diabetes, a condition which can be caused by obesity.
Professor Lee Roberts, who supervised the research, said: “Although this research is at an early stage, our discovery may form the basis of new therapies or therapeutic approaches to prevent the development of cardiovascular and metabolic diseases such as diabetes in people with elevated blood fats in obesity.”
In the lab, the team replicated the blood lipid levels observed in humans with metabolic disease by exposing skeletal muscle cells to palmitate, a fatty acid. The cells began to transmit the ceramide signal.
When these cells were mixed with others which had not been previously exposed to lipids, the researchers found that they communicated with each other, transporting the signal in packages called extracellular vesicles.
The experiment was reproduced in human volunteers with metabolic diseases and gave comparable results. The findings provide a completely new angle on how cells respond to stress, with important consequences for our understanding of certain metabolic diseases including obesity.
Professor Roberts said: “This research gives us a novel perspective on how stress develops in the cells of individuals with obesity, and provides new pathways to consider when looking to develop new treatments for metabolic diseases.
“With obesity an ever-increasing epidemic, the burden of associated chronic disease such as type 2 diabetes necessitates new treatments. We hope the results of our research here open a new avenue for research to help address this growing concern.”
To prevent diabetic foot ulcers, scientists at the University of Texas at Arlington have developed responsive footwear technology that relieves pressure on areas of the feet that experience high stress during walking and other activities.
Principal research scientist Muthu Wijesundara and his team have received a patent for a dual-layer insole apparatus for diabetic foot lesion prevention.
Due to numbness in their legs and feet, people with diabetes often are unable to detect and respond to stress-related pain by adjusting their foot loading. This can result in repeated stress to high-pressure foot regions such as the heel or toes and can worsen blisters, sores and ulcers to the point of severe tissue loss or life-threatening infection. For many, foot ulcers can lead to amputation of a toe, foot or leg.
“Diabetes is a leading cause of amputation worldwide, and there is a major role that technology can play to prevent its devastating effects,” Wijesundara said. “We are now one step closer to finding a solution to reduce risk of complications related to diabetic foot ulcers.”
The removable shoe insole relieves stress by periodically regulating and redistributing pressure across all areas of the foot. Using fluid-filled cells, the dual-layer apparatus provides variability in a person’s foot-loading patterns to reduce prolonged pressure to any given area. The insole can automatically adjust and is designed to accommodate people of various weights.
Additionally, the insole can be substituted for a total contact cast during the healing of a foot ulcer, and it can provide gait and ground force analysis.
In a study published in Hypertension, Osaka University researchers have demonstrated an association between the use of mineralocorticoid receptor antagonists (MRAs) and an improved renal prognosis in individuals with chronic kidney disease CKD in real-world settings.
As CKD progresses, the initiation of renal replacement therapy (RRT), which includes dialysis and kidney transplantation, may be necessary for life support in kidney failure. MRAs, which include spironolactone, eplerenone and potassium canrenoate, are commonly used to reduce swelling, blood pressure, and urine protein levels in people with CKD. However, the study was motivated by a lack of information on the link between MRA treatment and the initiation of RRT in a real-world population.
“We conducted a retrospective analysis of clinical data from over 3100 individuals with CKD,” explained lead author Tatsufumi Oka. “We evaluated MRA treatment in various populations of people with CKD, including those with diabetes, heart disease, and severely impaired renal function.”
The research team made use of a marginal structural model to analyse the association between MRA use and the initiation of RRT across multiple patient subgroups.
“Our analysis showed that MRA use was associated with a 28% lower rate of RRT initiation and a 24% lower rate of the combined outcomes of RRT initiation and death,” says senior author Jun-Ya Kaimori.
The researchers found a reduced risk for RRT initiation across various subgroups of people with CKD, including those with and without diabetes and those with severely impaired renal function. These findings highlight the association of MRA use and improved renal outcomes in a real-world population of CKD patients with varying health backgrounds. Overall, the study findings support the use of MRAs in treatment plans for various groups of people with CKD who are not undergoing dialysis.
Nursing home residents with diabetes are at high risk of having hypoglycaemia if their diabetes is overtreated, finds a new study published in the Journal of the American Geriatrics Society. The research suggests that many residents of nursing homes continue to receive insulin and other medications that increase hypoglycaemia risk even after blood tests suggest overtreatment.
Among 7422 nursing home residents, most had blood test results at the start of the study suggesting tight control of their blood sugar levels, and most were on insulin. Only 27% of overtreated and 19% of potentially overtreated residents at baseline had their medication regimens deintensified within 2 weeks.
Long-acting insulin use and hyperglycaemia ≥300 mg/dL before index HbA1c were associated with increased odds of continued overtreatment. Severe functional impairment (MDS-ADL score ≥ 19) was associated with decreased odds of continued overtreatment Hypoglycaemia was not associated with decreased odds of overtreatment.
The researchers suggested that deprescribing initiatives targeting residents at high risk of harms and with low likelihood of benefit, such as those with history of hypoglycaemia, or high levels of cognitive or functional impairment are most likely to identify nursing home residents most likely to benefit from deintensification.
“I hope this work lays the foundation for future projects that promote appropriate deintensification of glucose lowering medications in nursing home residents,” said lead author Lauren I. Lederle, MD, of the San Francisco VA Medical Center.