Diabetes, Obesity and Metabolism Now最新文献

Muscle loss and sarcopenia is increasingly prevalent especially in the ageing population and is a recognized independent factor for increased risks of morbidity and mortality. Previous evidence have shown that diabetes accelerates sarcopenia. This is relevant since diabetes has increasingly become one of the most important problems affecting the elderly, leading to increased risks of weakness, frailty, and adverse health outcomes. Strategies to understand the mechanisms of and the prevention of muscle loss is therefore important. Furthermore, developing a therapeutic solution that could properly target both disuse atrophy and muscle recovery may improve health outcomes following surgery or period of inactivity.

A recent study published in the journal Aging Cell [1] by researchers from the University of Utah have shown that Metformin, has surprising applications on a cellular level to target muscle loss. It works by targeting so called senescent cells, which impact muscle function. Senescent cells secrete factors associated with inflammation that may underlie muscle fibrosis. In younger, healthier people, short-term senescence is important for recovery from injury, and completely blocking the senescent effect impedes the body's efforts to heal. Conversely in the ageing, immune dysfunction results in reduced clearance of senescent cells and hence a slower recovery for the elderly after periods of disuse. Metformin's anti-senescent properties have previously been demonstrated through pre-clinical studies. To test the intervention in humans in the present study, the researchers randomized 20 individuals to receive metformin (N = 10) or placebo (N = 10) and participants undergo a muscle biopsy and MRI before and after the intervention, which involved 5 days of bed rest. All patients then completed a seven-day re-ambulation period followed by a final muscle biopsy.

The study showed that participants who took Metformin during a bed rest had less muscle atrophy and during the recovery period, their muscles also had less fibrosis or excessive collagen. Participants who took Metformin had fewer markers of cellular senescence which may explain the mechanism of the observed effects. Further studies are ongoing to incorporate the anti-senescence effects of metformin with leucine, an amino acid that promotes growth and could accelerate recovery even further. Evidence based from these experimental studies may form the basis for wider clinical studies to investigate the efficacy of metformin to prevent muscle loss and frailty as a result of disuse atrophy.

Tirzepatide, a dual GLP-1, GIP uni-molecular agonist had previously shown a significant ~22% weight loss in the SURMOUNT-1 pivotol trial and received FDA approval in 2022. The percentage weight loss observed in that study was indeed the largest weight loss seen in an anti-obesity, weight loss trial to date. Previous studies have also shown that the efficacy of anti-obesity drugs to induce weight loss in people with type 2 diabetes is typically less when compared to people without type 2 diabetes. The largest weight loss seen in overweight/obese people with type 2 diabetes was previously observed with Semaglutide 2.4 mg (Wegovy) in the STEP-2 trial. Previous large-scale trials with tirzepatide in people with type 2 diabetes in the SURPASS programme did not focus patients with type 2 diabetes who are also overweight or obese. Against this background, the SURMOUNT-2 pivotal trial investigated the efficacy of tirzepatide in people with type 2 diabetes who are also overweight/obese. The result of this important trial was presented at the American Diabetes Association (ADA2023) meeting. The trial reported that weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%–14.7% in-trial weight loss for 10 and 15 mg of tirzepatide respectively after 72 weeks—a finding that will likely lead to US Food and Drug Administration (FDA) approval of a new indication for weight loss for tirzepatide. The observed weight loss of approximately 15% from baseline was the first to be seen with any anti-obesity therapy in people with type 2 diabetes. Amazingly, up to 34% of patients achieved >20% weight reduction. As in the SURPASS trial programme, the greatest rate of weight loss was seen in the first 24 weeks of treatment. This magnitude of weight loss throughout the study was associated with approximately 2.1% absolute HbA1c reduction. In addition to weight and HbA1c reduction, all key secondary end-points that included systolic blood pressure, lipid parameters, fasting glucose and waist circumference, were all met. While direct head-to-head comparison between studies was not possible, these findings easily placed Tirzepatide, marketed as Mounjaro in a favourable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy) for weight loss. This new findings therefore support the assertion that tirzepatide is currently the most effective agent currently on the market to help achieve the two co-primary goals for patients with type 2 diabetes—weight loss and glycaemic control—while also having favourable effects on cardiovascular risk factors. The study is published in the Lancet.^[1]

Semaglutide is a GLP-1 analogue peptide which has been used and approved to treat overweight, obesity or type 2 diabetes for many years as a once weekly subcutaneous injections. The oral formulation of semaglutide (Rybelsius) is also now available and currently approved at a maximum dose of 14 mg/day. In a previous phase 2 dose ranging studies however, additional weight loss was observed at doses higher than 14 mg/day. Two trials—the OASIS, in patients with overweight or obesity without type 2 diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were therefore conducted to evaluate the efficacy and safety of higher doses of oral semglutide at 25 and 50 mg/day to induce weight loss and improvement of other metabolic parameters. Both phase-3 studies were presented at the American Diabetes Association (ADA) 83rd Scientific Sessions and simultaneously published in The Lancet. OASIS-1^[1] showed that oral semaglutide 50 mg produced a mean % weight reduction of 15.1% compared with −2.4% with placebo. Adverse events were marginally more frequent with oral semaglutide, driven by largely gastrointestinal side effects (80% with oral semaglutide vs. 46% with placebo) and gall bladder and biliary related disorders (11.1% with oral semaglutide vs. 3.6% with placebo). The PIONEER PLUS trial^[2] meanwhile showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 and 50 mg) compared with the currently [highest] approved 14-mg dose. Hba1c reduction was reduced by −1.5%, −1.8% and −2.0% with oral semaglutide 14, 25 and 50 mg, respectively. These two studies therefore showed the safety and efficacy of oral semaglutide to treat obesity and type 2 diabetes, with results comparable to the use of injectable semaglutide 2.4 mg once weekly. Due to the lack of availability of injectable semaglutide worldwide, it is thought that availability of an efficacious ‘pill’ might have a larger global reach and increase access to care as well as provide opportunities to individualized care especially for individuals who struggle with the use of injectable therapies. However, its effect on reducing cardiovascular outcomes remains unclear. Studies are ongoing to clarify this important clinical and research question.

Amylin is co-stored and co-secreted with insulin by pancreatic islet β-cells. It inhibits food intake, delays gastric emptying and decreases blood glucose levels, leading to the reduction of body weight—all similar to actions of GLP-1 analogue. Previous dose ranging studies of Amylin analogue, Cagrilintide have shown efficacy to induce weight loss. In a phase 2 study presented at the American Diabetes Association (ADA) 83rd Scientific Sessions, and simultaneously published in The Lancet,^[1] the efficacy and safety of combining the GLP_1 analogue Semaglutide with Cagrilintide in people with type 2 diabetes was reported. The primary endpoint of the study was HbA1c reduction and secondary endpoint was weight loss. At 32 weeks, HbA1c reduction was reported to be −2.2%, −1.8% and −0.9% for CagriSema, semaglutide and Cagrilintide, respectively. Remarkably, % weight loss was a staggering −15.6% with Cagrisema compared to −5.1% and −8.1% with semaglutide and cagrilintide, respectively. Surprisingly, the gastrointestinal events was low—likely due to slower dose titration. The weight loss data here seems staggering and not previously reported with pharmacotherapies in this population, reassuringly with an acceptable safety profile. These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies.

While the availability of peptides targeting GLP-1 and GIP receptors have revolutionized the management of obesity in patients with or without type 2 diabetes, peptides can easily be degraded by multiple enzymes in the stomach and the intestines as well as having low permeability across intestinal epithelium. Thus, to ensure optimal plasma therapeutic levels, majority of peptides are given by subcutaneous injections for clinical use. Where oral peptide formulations are available, such as the GLP-1 analogue, Rybelsius, patients will need to be educated properly to take their tablets on an empty stomach with minimal amount of water to ensure optimal absorption. To ensure further individualization of care especially where patients are not be able to religiously comply with instructions for oral peptide administration, data are needed regarding the efficacy and safety of the non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist. In a phase 2 study presented at the ADA meeting and simultaneously published in the New England J of Medicine,^[1] orfoglipron as a once daily oral therapy was investigated for weight reduction in adults with obesity. In this study, participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36 or 45 mg) or placebo once daily for 36 weeks. At week 26 (primary end-point), the mean change from baseline in body weight ranged from −8.6% to −12.6% across the orforglipron dose cohorts and at week 36 (secondary end-point), the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo. Importantly, the use of orforglipron led to improvement in all pre-specified weight-related and cardiometabolic measures and the adverse effect and safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. Importantly, weight loss with orforglipron did not appear to plateau at the 36-week mark in the trial and later-phase studies are currently underway to evaluate the drug for longer to assess its full efficacy. The data seemed to provide preliminary evidence that this non-peptide oral GLP-1 agonist orfogliprin produced.

Recent years have seen the development of technology for the management of patients with type 1 diabetes. One such technology is the closed-loop control systems of insulin delivery. Also known as the ‘artificial pancreas’, this is a system where an insulin pump and a continuous glucose monitor ‘talk’ to each other via a computer algorithm inside a phone or a pump. While evidence for efficacy and safety for this technology in adults or adolescents with type 1 diabetes have been established, the efficacy and safety of initiating a closed-loop system in young children remains unclear. In a 13-week multicentre trial published in the New England J Medicine,¹ children aged 2–6 years were randomly assigned in a 2:1 ratio to receive treatment with a closed-loop system of insulin delivery or standard care that included either an insulin pump or multiple daily injections of insulin plus a continuous glucose monitor. The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg/dL (3.9 to 10 mmol/L), as measured by continuous glucose monitoring. Secondary outcomes included the percentage of time that the glucose level was above 250 mg/dL (13.9 mmol/L) or below 70 mg/dL (3.9 mmol/L), the mean glucose level, HbA1c level, and safety outcomes. A total of 102 children underwent randomization (68 to the closed-loop group and 34 to the standard-care group). Baseline HbA1c ranged from 5.2% to 11.5%. The mean (±SD) percentage of time that the glucose level was within the target range increased from 56.7 ± 18.0% at baseline to 69.3 ± 11.1% during the 13-week follow-up period in the closed-loop group and from 54.9 ± 14.7% to 55.9 ± 12.6% in the standard-care group (mean adjusted difference, 12.4%) Benefits of close loop system was also seen in the percentage of time that the glucose level was above 250 mg/dL (13.9 mmol/L), on the mean glucose level, and on the HbA1c reduction, with no significant between-group difference in the percentage of time that the glucose level was below 70 mg/dL (3.9 mmol/L). Two cases of severe hypoglycaemia in the closed-loop group and one case in the standard-care group was observed. In addition, one case of diabetic ketoacidosis occurred in the closed-loop group. Overall, this trial provided strong evidence for the safety and efficacy of the hybrid close-loop system for young children with type 1 diabetes compared with standard care.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; PEDAP ClinicalTrials.gov number, (NCT04796779).

Exercise improve blood glucose levels in people with type 2 diabetes, reduces cardiovascular risk factors, contributes to weight loss, and improves well-being. Current guidelines recommend that most adults with diabetes should engage in 150 min or more of moderate-to-vigorous intensity exercise weekly, spread over at least 3 days/week, with no more than two consecutive days without exercise. However, the best timing of exercise activity is unclear. The Look AHEAD (Action for Health in Diabetes) trial was the largest randomised trial evaluating a lifestyle intervention in older adults with type 2 diabetes compared with a diabetes support and education control group. The intensive lifestyle intervention group underwent at least 175 min/week of unsupervised exercise. Although major cardiovascular events were the same in both groups, (likely due to greater use of cardioprotective medications in the diabetes support and education group), the intensive lifestyle intervention group achieved significantly greater sustained improvements in weight loss, cardiorespiratory fitness, blood glucose and blood pressure levels, and provided very strong evidence of profound health benefits from intensive lifestyle intervention. In a further analysis of the Look AHEAD study, researchers from the Brigham and Joslin Diabetes Centre assessed whether physical activity at certain times of day was associated with greater improvement in blood glucose control. The investigators analysed physical activity data from the first and fourth years of the Look AHEAD study, which included data from over 2400 participants. During the study, participants wore a waist accelerometry recording device to measure physical activity. Comparing data from year 1 and year 4 of the study, the investigators observed that those who engaged in moderate-to-vigorous physical activity in the afternoon had the greatest reduction in blood glucose levels, maintained these reductions in blood glucose levels and were more likely to stop their glucose-lowering/diabetes medications. The study was published in the journal Diabetes Care.¹ While the study has limitations due to its residual confounding effects such as impact of circadian rhythm, sleep, dietary intake and occupation, this study provided additional understanding on the importance of timing of physical activity on exercise induced blood glucose lowering.

This study was funded by the National Heart, Lung, and Blood Institute (K99-HL-148500, R01-HL140574), National Institute on Aging (RF1AG059867 and RF1AG064312), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (K23-DK114550).

Losing weight with lifestyle changes in an intensive behavioural weight loss programme was associated with a decrease in risk factors for cardiovascular disease and Type 2 diabetes for at least 5 years—even if some weight was regained, according to a systematic review of research, published today in Circulation: Cardiovascular Quality and Outcomes, a peer-reviewed American Heart Association journal.

Individuals with obesity have a higher risk of developing cardiovascular risks due to adverse cardiovascular risk factors such as insulin resistance, high cholesterol and high blood pressure. Whilst lifestyle interventions such as dietary, exercise and behavioural intervention can help people lose and maintain a healthy weight, many patients experience weight regain. Some observational studies suggest that weight regain may increase cardiovascular risk but data from randomized trials and long-term follow-up studies is lacking.

A systematic review, published in the journal Circulation: Cardiovascular Quality and Outcomes, assessed international scientific studies available in 2018 to compare risk factors for cardiovascular disease and Type 2 diabetes amongst people who followed an intensive behavioural weight loss programme to those who followed a less intensive or no weight loss programme. The studies in the analysis included diet and/or exercise interventions, partial or total meal replacement, intermittent fasting, or financial incentives contingent on weight loss. A total of 124 studies involving more than 50 000 participants, with an average follow-up of 28 months were included in the analysis. Mean age at baseline was 51 years old with a body mass index of 33. The average weight loss across the different studies ranged from 2–5 kilogrammes. Weight regain averaged 0.12 to 0.32 kg/year.

Compared to people in a less intensive programme and those in no weight loss programme, participants who lost weight through an intensive weight loss programme had lower risk factors for cardiovascular disease and Type 2 diabetes, which persists for 5 years after weight loss intervention. Crucially, the decreased risk of being diagnosed with cardiovascular disease or Type 2 diabetes also appeared to remain lower even after weight regain. This finding provided some reassurance that weight loss programmes are effective in reducing cardiovascular risk factors even after some weight regain. The study also has relevance due to the well-recognized risks of weight regain following short term pharmacological intervention. Whether these temporary improvements in weight and cardiometabolic risk factors after weight loss intervention lead to long-term clinical benefit however remains unclear.

Bariatric surgery is increasingly been utilized to induce and maintain significant weight loss among patients with obesity. For patients with diabetes, bariatric surgery is associated with increased likelihood of reversal of type 2 diabetes; however, its impact on long-term diabetes related neuropathic complications remain unclear. This is particularly relevant given the potential increased risk of “treatment-induced neuropathy” associated with rapid improvements of glucose control. A study undertaken by research team from the University of Michigan have now reported that bariatric surgery may improve neuropathy by regenerating damaged nerves. In the study published in the journal Diabetologia, 120 patients who underwent bariatric surgery for obesity were followed up for over 2 years after the procedure. Metabolic risk factors such as high glucose, high blood pressure and lipid levels were significantly improved. The researchers also assessed two primary measures for peripheral neuropathy in patients with obesity by undertaking skin biopsies to assess nerve fibre density in the thigh and the leg. They observed that 2 years after bariatric surgery, nerve fibre density improved in the thigh and remained stable in the leg. This is particularly relevant given that the natural history of peripheral neuropathy among patients with obesity is often associated with a decline in nerve function, thus, stability in nerve fibre density is considered to be a good outcome. Furthermore, the observed improvement in nerve fibre density at the thigh indicate that bariatric surgery may be a successful therapy to improve or reverse peripheral neuropathy for patients with long-term metabolic impairment. This finding advances current therapeutic options for peripheral neuropathy, especially in patients with obesity which currently focuses on analgesia and neuropathic oral treatment such as gabapentin, amitriptyline, duloxetive, topical analgesics and non-medical treatments, like acupuncture and cognitive behavioural therapy.

Increased evidence has emerged regarding the cardio- and renal protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitor. However, this class of therapy is also associated with potential increased risk of adverse effects–namely genito-urinary tract infection, dehydration and rarely, increased risks of DKA. Despite these potential adverse effects, little is known about their effects on hospitalization from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease. A recent sub-analysis of the DECLARE-TIMI trial assessed the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease. Between 2013 and 2018, 17 160 people were enrolled in the original trial, of whom 10 186 had multiple risk factors for atherosclerotic cardiovascular disease, and 6835 had both no evidence of atherosclerotic cardiovascular disease and low kidney disease risk. According to the results, dapagliflozin was associated with a lower risk of first non-elective hospitalization for any cause and total non-elective hospitalisations for any cause. The association between dapagliflozin use and the risk of first non-elective hospitalization for any cause was consistent in subgroups of participants with and without atherosclerotic cardiovascular disease at baseline. In addition, compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders, metabolism and nutrition disorders, renal and urinary disorders, and due to any other cause excluding these three causes. Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders and infections. These findings might have important implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition.