Diabetes, Obesity and Metabolism Now最新文献

Achieving tight glucose control during pregnancy is important in order to reduce maternal and neonatal complications such as premature labour, large birthweight and neonatal hypoglycaemia. As such, target glucose level is often set to be more stringent when compared with non-pregnant levels. Glycaemic control, however, is often more challenging during pregnancy due to unpredictable eating patterns, reduced physical activity and secretions of placental hormones linked to insulin resistance. For many patients, the use of standard multiple insulin injections a day and/or insulin pump therapy is still quite onerous due to the need to make insulin adjustments often more than five times a day. A closed-loop system, however, automatically adjusts insulin levels according to blood glucose levels every 10 min, but their efficacy during pregnancy remains unclear.

A new study, published in the New England Journal of Medicine,¹ has found that pregnant women using hybrid closed-loop system spend 2.5 more hours per days in the target blood sugar range compared with standard therapy, with no unexpected safety issues being reported. This randomized controlled trial included 124 pregnant women with type 1 diabetes from nine hospitals in England, Scotland and Northern Ireland. The mean age was 31 years, and 93% of the participants were White. Before 16 weeks' gestation, participants were randomized to a standard insulin pump (N = 63) and a closed-loop system (N = 61) with both groups having continuous glucose monitoring on their phone.

The study found that those on the closed-loop group spent 12% more time within the target blood sugar range for pregnant women (3.5–7.8 mmol/L) than the participants in the standard pump group (68% vs. 56%). Additionally, the pregnant women in the closed-loop group spent less time above range (29%) than those in the standard pump group (41%), had more overnight time in the target range (difference, 12.3%) and had lower HbA1c level (difference, −0.31%). Little time was spent in a hypoglycemic state. Interestingly, women who used the closed-loop system gained 3.7 kg less weight during pregnancy.

In my opinion, this is a landmark study on the best strategy to optimize glycaemic control in pregnancy. This study provides clear and compelling benefits of using hybrid closed-loop technology during pregnancy for people with type 1 diabetes. As such, the UK National Institute of Health and Care Excellence has now recommended closed loop as an option for all women with type 1 diabetes who are pregnant or planning pregnancy.

Epigenetic changes arise due to changes in environmental and lifestyle factors and can affect the function of genes. Whether epigenetic changes cause type 2 diabetes or is simply a marker of having type 2 diabetes remains a matter of debate. In addition, if epigenetic changes do cause type 2 diabetes, what genes were involved? A new study¹ by researchers at Lund University published in Nature Communications provides support for the idea that epigenetic changes can cause type 2 diabetes and have identified new genes that impact the development of the disease. The researchers studied epigenetics in pancreatic islet cells from donors and found 5584 (DNA methylation) sites in the genome with changes that differed between 25 individuals with type 2 diabetes and 75 individuals without the disease. The same epigenetic changes found in people with type 2 diabetes were also found in individuals with elevated blood sugar levels, which increase the risk of developing the disease. Since these same epigenetic changes were observed in people with type 2 diabetes and individuals at risk for the disease, it was concluded that these epigenetic changes were likely to contribute to the development of type 2 diabetes. The study therefore identified 203 genes with different expression in individuals with type 2 diabetes compared to the control group. The researchers found that the gene RHOT1 showed epigenetic changes in people with type 2 diabetes and that it also played a key role in insulin secretion in pancreatic islet cells. This was supported when the deletion of the gene expression of RHOT1 resulted in decreased insulin secretion. Having identified genes involved in the epigenetic changes, the next step was to develop a blood-based biomarker that can predict who is at risk of developing type 2 diabetes. To this end they investigated whether the epigenetic changes from the human pancreatic islet studies were reflected in blood of living people. They found that epigenetic changes in the blood of 540 people without the disease could be linked to the future development of type 2 diabetes in half of the individuals. Factors such as unhealthy diet, sedentary lifestyle, and ageing increase the risk of type 2 diabetes, and they also affect our epigenetics.

The development of a reliable epigenetic marker will enhance the ability to identify individuals who are at high risk of developing type 2 diabetes so that a more focused and aggressive intervention could be put in place to reduce the risk of developing type 2 diabetes. Alternatively, new methods can be develop to correct the activity of certain genes using epigenetic editing.

Type 2 diabetes and obesity are both independently associated with an increased risk of colorectal cancer. A study conducted by researchers at Case Western Reserve University published in the journal JAMA Oncology has now reported that GLP-1 may reduce the risk of colorectal cancer.¹

Using a national database to identify more than 100 million patients electronic health records, the researchers conducted a population-based study of 1 221 218 patients with type 2 diabetes. Patients were prescribed with anti-diabetic agents from 2005 to 2019 and had no prior antidiabetic agents (drug naïve) use and no previous history of colorectal cancer. The cohorts were propensity-matched, to adjust for demographics, adverse socioeconomic determinants of health, preexisting medical conditions, family and personal history of cancers and colonic polyps, lifestyle factors (exercise, diet, smoking, and alcohol drinking), and procedures such as colonoscopy. Investigators then examined the effects of GLP-1 receptor agonist on their incidence of colorectal cancer compared to those prescribed with other anti-diabetic drugs. The outcome was the first diagnosis of colorectal cancer within 15 years of the first prescription of anti-diabetic therapies.

During a 15-year follow-up, among 22 572 patients treated with insulin, there were 167 case of colorectal cancer compared with 94 cases among matched number of patients receiving GLP-1 receptor agonist—a 44% reduction in the risk of developing colorectal cancer with a GLP-1 receptor agonist. Similarly, in a comparison of 18 518 patients with type 2 diabetes treated with metformin, compared to match number of patients with type 2 diabetes treated with GLP-1 receptor agonist, the latter was associated with a 25% reduction in the risk of developing colorectal cancer. Consistent findings were observed in women and in men. GLP-1RAs were also associated with a 50% lower risk for colorectal cancer in patients with obesity/overweight compared with insulin and 42% reduction compared with metformin.

While simple conclusion cannot be made from an observational study such as this, limited by the usual issues of un-adjusted confounders, evidence from this study could form a basis for the need for clinical trials to determine whether GLP-receptor agonist could prevent colorectal cancer. In addition, further study is required to investigate the mechanism for the potential benefit of GLP-1 receptor agonists to prevent colorectal cancer.

Diabetes, Obesity Metabolism (DOM) NOW – December 2023

Recent interest on very low calorie diet and bariatric surgery for the treatment of overweight/obese patients with type 2 diabetes have provoked interest to achieve diabetes remission as a treatment target. In addition, overweight and obese patients are often encouraged to lose weight to improve their diabetes outcomes. A study from Korea, which was published in Diabetes, Obesity & Metabolism,¹ however, have highlighted the important of early weight loss to enhance the likelihood of inducing diabetes remission.

The study was a retrospective real-world outcomes study derived from database of the Korean National Health Insurance Service. It examined the weight and health outcomes of 114 874 people in Korea who were diagnosed with type 2 diabetes between 2009 and 2012. Participants were then followed up until 2017. More than 23 000 of the participants lost more than 5% of their body weight. 2429 (2.1%) of the participants achieved remission during the trial, defined as fasting blood glucose less than 126 mg/dL (7 mmol/L) at two or more consecutive health examinations after stopping medication. The adjusted odds ratio for remission in the weight loss group was 2.56 (95% confidence interval 2.35–2.79) compared with the group with stable body weight. The greater weight loss the higher the likelihood of remission indicating that diabetes remission was driven primarily by weight loss. The effects of weight loss on remission were significantly greater in subgroups of age <65 years, male sex and body mass index >25. Weight loss within the first 2 years of treating type 2 diabetes mellitus was associated with diabetes remission. This study, therefore, highlights the importance of aggressive weight management from the outset of diabetes diagnosis to increase the likelihood of diabetes remission. I would suggest that such aggressive management to induce significant weight loss is not dissimilar to the early intensive management of hyperglycaemia due to the well-recognized ‘legacy effect of hyperglycaemia’.

Diabetes, Obesity Metabolism (DOM) NOW – December 2023

Conclusive evidence have shown the cardiovascular benefits of semaglutide (1 mg weekly) in people with type 2 diabetes.¹ Recent data have also confirmed the efficacy of high dose semaglutide (2.4 mg weekly) to induce significant weight loss in people without type 2 diabetes,² but the cardiovascular benefits of semaglutide in people without type 2 diabetes remains unclear. A new study published in the New England Journal of Medicine (Select Trial)³ have now reported the cardiovascular benefits of semaglutide in overweight/obese people without type 2 diabetes.

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT)³ is a multicentre, double-blind, randomized, placebo-controlled, that enrolled more than 17 000 patients aged 45 years of age or older who had pre-existing cardiovascular disease and a body-mass index of 27 or greater but no history of diabetes. Patients were randomly assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for an average of 3 years (mean duration of exposure to semaglutide or placebo was ~34 months, and the mean duration of follow-up was ~40 months). The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. The trial showed a significant 20% reduction of developing a primary cardiovascular end-point in the semaglutide group compared with the placebo group. Importantly, the difference in rates between the two treatment groups began to emerge within the first months of treatment. Consistent trends were also observed for each component of the composite primary outcome in addition to death from any cause (i.e., non-fatal stroke, non-fatal heart attack). The study also observed reduction in coronary revascularization and kidney function deterioration among those assigned semaglutide 2.4 mg. Not surprisingly, mean change in body weight after 104 weeks was greater in the semaglutide group −9.4%, compared with −0.9% in the placebo group. There was also a reduction in progression to diabetes and pre-diabetes with semaglutide 2.4 mg. However, adverse events leading to permanent discontinuation of the trial product occurred twice more in the semaglutide group (16.6%) compared with placebo (8.2%); which was significant. The difference was driven almost entirely by differences in gastrointestinal side effects. Reassuringly, there was no increase in adverse events of special interest, including acute pancreatitis and gallbladder-related events, cancers or psychiatric disorders.

This study is the largest and longest trial with the most data for this group of patients. How much can we generalize the findings from this study in the overweight/obese patient group? Well, the m

Diabetes, Obesity Metabolism (DOM) NOW—November 2023

Physical activity is an important life-style measure to reduce risks of developing type 2 diabetes. However, the most effective timing, consistency and intensity of physical activity is still not known. To investigate this, a study was undertaken using a cohort of 93 095 UK Biobank participants (mean age 62 years) without a history of type 2 diabetes. All participants wore a wrist-worn accelerometer for 1 week and the investigators converted accelerometer information to estimate metabolic equivalent of task (MET) (a common measure of physical activity), summing MET-hours of total physical activity. MET-hour physical activity captures all types of activity undertaken by an individual throughout the day and is measured with the accelerometer, including chores, walking, and vigorous activity. The investigators measured completed METs within three time segments (morning, afternoon, and evening), divided as 06:00–12:00 h (morning); 12:00–18:00 h (afternoon); and 18:00–24:00 h (evening). Consistency of physical activity was analysed by measuring difference of each person's activity from their own personal average. Those with smaller deviations (variance) were considered to be more consistent. The authors also classed the intensity of exercise to moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA) in association with type 2 diabetes incidence.

Using these analyses, 10% and 9% reduction in risk of type 2 diabetes was seen with morning and afternoon activity, respectively but no statistically significant association was observed between evening physical activity and risk of type 2 diabetes. The reason for this observation is unknown but the investigators speculate that lifestyle factors, such as the amount of sleep and dietary intake, would influence the amount of physical activity in the morning, afternoon, and evening undertaken, and therefore the role activity has in the risk of developing type 2 diabetes. When adjusting for lifestyle factors, the observed associations for MET-hours with different times of day became more precise. Consistency of MET-measured physical activity however was not associated with type 2 diabetes; but intensity was—both MVPA and VPA were associated with decreased risk for type 2 diabetes at all times of the day.

While the study has known limitations—for example, retrospective nature, residual confounding and selected populations, this is the first study to report that the timing of activity may play a role in the mitigation of diabetes risk. In addition, total physical activity but not its consistency over the week is an important factor that influences the risk of developing type 2 diabetes, in other words, individuals who exercise a smaller amount of time more frequently have a similar reduced risk of developing type 2 diabetes as individuals who exercise the same total amount, but with less of a routine. Evidence

Diabetes, Obesity Metabolism (DOM) NOW—November 2023

The dual GLP-1 and GIP agonist, Tirzepatide has been shown to induce significant weight loss in overweight/obese people with or without type 2 diabetes. Much of its efficacy was derived from The SURMOUNT program which included four global phase 3 trials NCT04184622 (SURMOUNT-1), NCT04657003 (SURMOUNT-2), NCT04657016 (SURMOUNT-3) and NCT04660643 (SURMOUNT-4). In these studies, participants were randomized to once-weekly subcutaneous tirzepatide versus placebo in a double-blind manner. The primary end point in all trials was the percentage change in body weight from randomization to end of treatment. Results for the primary endpoint for SURMOUNT-1¹ (in overweight/obese people without type 2 diabetes) and SURMOUNT 2² (in overweight/obese people with type 2 diabetes) have been published. The magnitude of weight loss with Tirzepatide was generally superior to single GLP-1 agonists, that is, −2.8% and −14.7% weight reduction in people with type 2 diabetes and − 19.5% and − 20.9% weight reduction in people without type 2 diabetes, at 10 and 15 mg doses of Tirzepatide respectively for both studies. Whether weight lost persists with continuation of the therapy or weight regain following discontinuation of the treatment is unclear.

In a presentation at the European Association of the Study of Diabetes (EASD) meeting, results of the SURMOUNT-4 trial was presented. In this study, 783 adults with obesity or overweight but did not have diabetes who all took the drug for 36 weeks were randomized to continue taking it for another 52 weeks or to stop taking treatment. Those who were randomized to continue taking the therapy experienced a mean total weight loss of 26.0%, whereas those randomized to discontinue taking the drug and switch to placebo regained some weight but still maintained a 9.5% weight loss from baseline by 88 weeks. No unexpected adverse effects were reported. The observed weight loss in this latest study at 88 weeks is the largest that has been seen using pharmacotherapy for weight loss and approaching to the amount of weight loss seen with the most common bariatric surgery procedure, sleeve gastrectomy. It is important to note, however, that weight regain was observed among people who discontinued the drug. Compared with a mean weight of 107.3 kg at baseline, participants' mean weight was 85.2 kg after 36 weeks. Those who discontinued tirzepatide regained weight to a mean of 97.0 kg whereas those who continued to take the drug achieved a mean weight of 79.1 kg. Therefore, although mean weight did not return back to baseline, the slope appeared to continue to rise and given enough time would probably get back to baseline eventually. Among participants who continued tirzepatide, 95% achieved at least 5% weight loss compared with 69% in the placebo group. In addition, 72.6% versus 11.6% of tirzepatide versus placebo recipients

Previous landmark studies have reported that the mechanism of remission of type 2 diabetes occurred as a results of weight loss which induced reduction in liver and pancreatic fat mass, leading to recovery of beta-cell function and insulin secretion. Such findings have led to interests in dietary, life-style and pharmacological intervention strategies to induce diabetes remission. Previous large scale randomized trials such as the diabetes prevention programme (DPP) have shown that life-style interventions was associated with a significant reduction in the risk of pre-diabetes progressing to diabetes state but the risks of relapse of pre-diabetes and subsequent progression to diabetes have not been studied. Furthermore, given that the beta-cell function in people with pre-diabetes remains intact (albeit being overworked), the mechanism of pre-diabetes remission remains unclear.

To investigate this, patients involved in the randomized, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) and who achieved weight loss-induced resolution of prediabetes was assessed and the results were validated against participants from the DPP study. The PLIS was conducted between between 1 March 2012 and 31 August 2016, and participants were recruited from eight clinical study centres (including seven university hospitals) in Germany. Patients were randomly assigned to receive either a control intervention, a standard lifestyle intervention (i.e., DPP-based intervention), or an intensified lifestyle intervention for 12 months. In a pre-specified post-hoc analysis of both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders or remission of pre-diabetes were defined as people who returned to normal fasting plasma glucose (FPG; <5.6 mmol/L), normal glucose tolerance (<7.8 mmol/L), and HbA_1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders or those whose pre-diabetes relapsed were defined as people who had FPG, 2 h glucose, or HbA_1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models.

Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% with 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Interestingly, while BMI reduction was similar between responders and non-responders, whole-body insulin sensitivity increased more in responders than in non-responders. Crucially, unlike studies in people with type 2 diabetes, insulin secretion did not differ within groups over time or between groups. Visceral adipose tissue (VAT) however decreased more in responders than in non-responders. Responders h

Recent advances in diabetes pharmacotherapy have provided clinicians with newer therapies to manage hyperglycaemia in patients with type 2 diabetes. Unlike previous agents, these new therapies such as sodium–glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) have been shown to provide cardio-renal benefits beyond their glucose lowering abilities. As well as their superior efficacy in lowering blood glucose levels in a glucose dependant manner (i.e., lower risks of hypoglycaemia), these agents have been shown to confer significant cardiovascular and renal benefits in addition to their weight loss effects. However, whether their efficacy was similar across different racial and ethnic groups remains unclear. To answer this question, researchers from Leicester have undertaken a systematic meta-analysis of 14 randomized placebo-controlled trials of SGLT2-Is and GLP1-RAs—seven trials for each drug—that had reported cardiovascular and renal outcomes by race or ethnicity.

Their study, published in the Journal of the Royal Society of Medicine (1) showed that for White and Asian populations, SGLT2-Is and GLP1-RAs had beneficial effects on blood pressure, weight control, and renal function, and significantly reduced the risk of major adverse cardiovascular events and kidney disease. Interestingly however, evidence of these beneficial effects in Black populations was not seen. Specifically, they reported no significant improvements for Black patients, with either drug, in the number of major adverse cardiovascular events, a composite CVD death/heart failure hospitalization measure, or the composite renal outcome (end-stage kidney disease, doubling of creatinine level, or death from renal causes), with the exception of a reduction in heart failure hospitalisations on SGLT2-Is. It is important to note however that the proportion of black patients is quite low (2.4% to 8.3%) compared with 66.6% to 93.2% for White populations, 1.2% to 21.6% for Asian populations, and 0.9% to 23.1% for ‘other’ populations. Thus, it seems that evidence from these landmark trials may be less generalizable to the black populations due to their under-representation in these trials. The latter is an important consideration because differences in the prevalence of type 2 diabetes (T2D), its risk factors, its microvascular and macrovascular complications, and associated mortality are well recognized between different ethnic groups. For example, Black people are more likely to develop T2D at a younger age, have higher risks of developing hypertension, more likely to have lower extremity amputations and to develop retinopathy and nephropathy. Whether observation from this study is mainly driven by low statistical power or due to genuine differences in genetic, pharmacokinetics, pharmacodynamics, and safety of SGLT2-Is and GLP1-Ras in this patient group is unknown. However it is important to note that Black populations are also

In this study,¹ concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured in the 2627 people who participated in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE). Investigators examined the effect of canagliflozin on biomarker concentrations as well as the prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min⁻¹·1.73 m⁻²], doubling of the serum creatinine level, or renal death or cardiovascular death).

The study showed that baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analysed together in a multimarker panel, individuals with high and moderate risk scores showed a higher risk for these outcome compared with those with low risk scores. By 1 year, a 50% increase in these biomarkers was associated with increased risk of the primary outcomes. Use of canagliflozin reduced the rise in each biomarker compared with placebo. A major limitations of the analysis however is that not all study participants in the trial had available samples for biomarker measurement. In addition, missing biomarker values during follow up may limit robust interpretation of the analysis. Nonetheless findings from this analysis provides some evidence and rationale to investigate the clinical utility of additional biomarkers as independent predictors of adverse cardiac and renal outcomes. In addition to providing individualized intensive treatment options to high risk patients, it may also provide some mechanistic understanding of how this drug class improved cardio-renal outcomes in people with type 2 diabetes and diabetic kidney disease.