Diabetes, Obesity and Metabolism Now最新文献

Previous studies have shown benefits of the Glucagon-like peptide (GLP-1) receptor agonist Semaglutide (Wegovy, Ozempic) to reduce cardiovascular events in overweight/obese people without type 2 diabetes.¹ However, whether these benefits occurred due to further reductions in glucose levels is unclear. Furthermore, the effects of Semaglutide on the risk of progression to Type 2 diabetes is not fully clarified.

Two recent analysis by the Select investigators published in the journal Diabetes Care have provided additional information on these research questions.

The first analysis was led by Dr Ildiko, Professor of Internal Medicine at the University of Texas Southwestern Medical Center in Dallas.² The analysis investigated the effects of Semaglutide on Major Adverse Cardiovascular events (MACE) (cardiovascular mortality, nonfatal myocardial infarction, or stroke; coronary revascularization; or hospitalization for unstable angina), a heart failure composite (heart failure hospitalization or urgent medical visit or cardiovascular mortality), coronary revascularization, and all-cause mortality) by baseline A1c subgroup and categories of A1c change. The analysis showed that similar reduction in MACE was observed irrespective of baseline HbA1c categorized at <5.7%, 5.7%–6.0% and 6%–<6.5%. Importantly also, the beneficial effects of Semaglutide was observed irrespective of whether HbA1c decreased or increased by 0.3% or remained unchanged after intervention.

While these findings would support the use of Semaglutide across a broader spectrum of glycaemia, it would be intriguing to understand whether these benefits are driven by the recognized metabolic benefits (blood pressure, cholesterol, insulin resistance) of weight loss. In addition, since albuminuria is recognized to occur due to obesity per se and has been shown to reverse with weight loss, it would be interesting to understand the impact of semaglutide on urine albumin excretion rate, an important causal and marker of endothelial function and cardiovascular disease risks.

In another analysis, investigators looked at the effect of Semaglutide on the progression of HbA1c level in this same study group over a 156 weeks period.³ They observed, while there was a clear effect of Semaglutide to improve glycaemia, (i.e. a smaller number with pre-diabetes at baseline progressed to diabetes, and a greater proportion regressed to normal HbA1c levels than those taking placebo), semaglutide did not slow glycemic progression over time. At 3 years, 69.5% of study participants taking semaglutide had a normal HbA1c level, compared with 35.8% of those taking placebo (p < .0001). Among those with a normal HbA1c level at baseline, 9 of 1676 participants (0.5%) receiving semaglutide developed type 2 diabetes (compared with 18 of 1690 placebo recipients). For those in the intermediate glycemia group

Fenofibrate is a PPAR α agonist which is widely used to treat hyperlipidaemia, specifically raised triglyceride. Previous sub-analysis of two large cardiovascular outcomes studies; The FIELD study¹ and the ACCORD study² have indicated potential benefits of Fenofibrate in retinopathy progression. The multicentre LENS trial is the first dedicated study investigating fenofibrate's effect on diabetic retinopathy outcomes³

In this study, a total of 1151 participants with either mild background retinopathy or maculopathy were randomly assigned to receive 145 mg fenofibrate or placebo either daily or every other day in those with impaired kidney function. 27% of participants had type 1 diabetes and 23% had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m². The primary outcome was time to the first occurrence of the composite of developing referable diabetic retinopathy or maculopathy, or treatment for diabetic retinopathy or maculopathy (including intravitreal injection of medication, retinal laser therapy, or vitrectomy) in either eye. The study showed that significant reduction in achieving primary outcome with fenofibrate compared with Placebo (hazard ratio 0.73, p = .006). The occurrence of any retinopathy or maculopathy progression was also significantly less common with fenofibrate, 32.1% versus 40.2% with placebo (hazard ratio [HR], 0.74), as was referral for treatment, 18.6% versus 25.9% with placebo (HR, 0.66). Significant reduction in developing macular oedema was also observed with fenofibtrate (HR, 0.50). No differences was observed between the two groups in visual function, quality of life, or visual acuity. Results were similar for participants with type 1 and type 2 diabetes, and those with normal versus impaired renal function.

Reassuringly, but perhaps unsurprisingly given that fenofibrate has been used widely in clinical practice, no safety concerns was observed. As anticipated, slight reduction in eGFR was observed in the fenofibrate group but this is reversible. It would be interesting to know if this mild reduction in eGFR would translate to long term renal protection, as was observed with SGLT2i and ACE-I therapy. Whether evidence derived from this work would translate to a change in routine practice especially within the ophthalmology circle remains clear. Among physician involved in managing people with type 2 diabetes a low threshold to start fenofibrate should be set especially among patients with diabetic eye diseases.

Glucagon-like peptide receptor agonist (GLP-1) is a highly effective treatment to improve glucose levels, induced significant weight loss and reduce vascular events. However, ongoing concerns persists regarding its effect to cause loss of lean muscle mass in conjunction with weight loss. Loss of muscle mass in the context of weight loss and weight (fat mass) regain thereafter, is associated with sarcopenic obesity, frailty and shown to be an independent predictor of morbidity and mortality especially in older adults. Furthermore, muscle is an important endocrine organ, accounting for ~70% of glucose disposal. Strategies to preserve loss of muscle mass in the context of GLP-1 therapy induced weight loss is therefore important and has recently gained a lot of interest.

To this end, a variety of medications is currently undergoing clinical trials for use with GLP-1 in people who are at risk of loss of muscle mass due to weight loss. A previous phase 2b trial comparing the antimyostatin intravenous therapy bimagrumab vs placebo have shown improvement in muscle mass but potential increased risk of acute pancreatitis. Another antimyostatin, apitegromab is also undergoing phase 2 trial, with another subcutaneous antimyostatin, taldefgrobep due to enter phase 2 trial this year.

The 2024 American Association of Clinical Endocrinology meeting presented some new data on the efficacy of the selective androgen receptor modulator (SARM), enobasarm in combination with a GLP-1 therapy. One study showed that 3 mg of enobasarm for 14 days in combination with GLP-1 increased total lean mass and decreased total fat mass in healthy young and older men (>60 years old). Another post-hoc analysis of a phase 3 clinical trial in people with advanced cancer showed that 3 mg/daily of enobasarm in a subset of participants aged >60 years with obesity showed reductions in fat mass while preserving lean body mass compared with placebo.

While these are important development, an important aspect that needs to be studied is the effects of these therapies on muscle function. This is important for regulatory approval due to a focus on true rather than surrogate endpoints. Furthermore, long-term safety of these new therapies remains unclear. For example, SARM has previously been shown to increased risks of cardiovascular events and thromboembolic diseases. Maintaining healthy lifestyle and muscle mass should therefore remain to be the mainstay of weight loss management. Studies on exercise intervention with GLP-1 however have provided heterogenous results, depending on type, duration and intensity of exercise interventions. Further studies are therefore needed to clarify the most effective, safe and durable strategy to induce weight loss while preserving loss of muscle mass.

Testosterone deficiency is well recognized to be associated with obesity, type 2 diabetes and the metabolic syndrome, all of which predisposes to increase risks of developing card

Diabetes, Obesity Metabolism (DOM) NOW–May 2024

It is well-recognized that exercise remains the cornerstone of management for people with type 2 diabetes and/or obese. In addition to support initiation and maintenance of weight loss and improvement in cardio-metabolic risk factors, engaging in regular moderate to vigorous physical activity have also been shown to contribute to improvement in cardio-metabolic risk factors, cardio-respiratory fitness, preservation of lean muscle mass as well as physical and mental well-being. While these maybe the case, there remains ongoing uncertainty with regards to whether morning, afternoon or evening timing may lead to greater improvements in cardio-metabolic outcomes. This is important since obesity and type 2 diabetes are associated with circadian misalignment and therefore impairment in metabolic processes. Previous RCT have reported that late-afternoon or evening aerobic exercise produce greater improvements in glycaemic outcomes but it is not known whether this translate to longer-term outcomes such as morbidity and mortality.

To answer this question, researchers analysed UK Biobank data of 29 836 participants with obesity (body mass index, › 30; mean age, 62.2 years; 53.2% women), including 2995 also diagnosed with T2D from a UK biobank accelerometry substudy.¹ Aerobic exercise was defined as bouts lasting ≥3 continuous minutes. Participants were categorized into morning (6 am–12 pm), afternoon (12 am–6 pm), or evening exercise (6 pm–12 am) based on when they undertook the majority of their aerobic exercise. The reference group included participants with an average of less than one aerobic exercise bout per day. Following adjustment for potential confounders, the association between the timing of aerobic physical activity and risk for all-cause mortality, CVD (defined as circulatory, such as hypertension), and microvascular complications (neuropathy, nephropathy, or retinopathy) was evaluated over a median follow-up of 7.9 years.

At follow-up, 1425 deaths, 3980 CVD events, and 2162 microvascular event occured. Compared with activity in the reference group, while afternoon and morning exercise produced lower mortality risk compared with reference group, evening exercise was associated with the lowest risk of mortality. The mortality risk was even lower in the type 2 diabetes subgroup. Similar patterns were observed for CVD and microvascular disease. Findings were similar in the Type 2 Diabetes subset.

This study therefore suggested that in addition to the total volume of exercise undertaken, its timing is also important in order to optimize cardiovascular, microvascular and mortality outcomes for people living with obesity or type 2 diabetes. Some limitation needs to be highlighted—this is an observational study with allocation and unadjusted confounding biases. In addition, participants from UK biobank may not be generalizable to the real world p

A new systematic review and meta-analysis study investigated whether adults with excess weight or obesity tend to experience higher levels of pain intensity than those with a normal weight.¹ The study was undertaken based on increasing evidence suggesting that obesity may alter pain perception and exacerbate existing painful conditions.² This is highly relevant since obesity per se is associated with pathophysiological changes such as increased load on joints and systemic inflammation, which may contribute to the pain experience.

In this study, investigators examined the association between overweight or obesity and self-perceived pain intensities. The study comprised of a meta-analysis of 22 studies that included 31 210 adults older than 18 years and from diverse international cohorts. The participants were categorized by body mass index (BMI) as being normal weight (18.5–24.9), overweight (25.0–29.9), and obese (≥30). Excess weight was categorized as those with a BMI >25. Pain intensity was assessed by self-report using the Visual Analog Scale, Numerical Rating Scale, and Numerical Pain Rating Scale, with the lowest value indicating “no pain” and the highest value representing “pain as bad as it could be”. Researchers then compared pain intensity between Normal weight vs overweight plus obesity, normal weight versus overweight, normal weight versus obesity, and overweight versus obesity.

Meta-analysis concluded that compared with people with normal weight, people with excess weight (overweight or obesity reported higher pain intensities, with a small effect size. No significance however was noted when comparison of self-report pain were conducted in people who had normal weight and overweight.

These findings therefore highlight the importance of treating obesity as an important strategy to alleviate pain and improve quality of life for patients who are obese. Further studies are required to clarify the underlying mechanism of increase pain perception among overweight and individuals living with obesity.

Diabetes, Obesity Metabolism (DOM) NOW—April 2024

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing and is fast emerging as one of the most important cause for progressive liver disease. Despite this, there has been no approved treatment until now.

Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist for the treatment of NASH with liver fibrosis. A previous phase 3 clinical trial (MAESTRO-NASH)¹ involving 966 adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 [stages range from F0 (no fibrosis) to F4 (cirrhosis)] was published in the New England Journal Medicine. Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 or 100 mg or placebo. The two primary end points at week 52 were NASH resolution [including a reduction in the nonalcoholic fatty liver disease (NAFLD) activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease] with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.

The study showed that NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group. Improvement in fibrosis was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group. The trial also met multiple secondary endpoints, including statistically significant reduction from baseline in liver enzymes (alanine transaminase, aspartate aminotransferase and gamma-glutamyl transferase) and low-density lipoprotein cholesterol with resmetirom compared with placebo.

Based on this, the US FDA has recently approved resmetirom (80-mg and 100 mg doses) to treat patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced liver fibrosis (consistent with stage F2 and F3 disease), along with diet and exercise. The most common adverse events included diarrhea and nausea, which typically began early in treatment and were mild to moderate in severity.

I believe that this approval for the first medication to treat MASH will form the basis for current and emerging pharmacological agents being studied as a therapeutic option to patients living with this serious liver condition. Further studies are ongoing to determine if the early beneficial effects of resmetirom could lead to reduced risk of progression to cirrhosis, liver failure and need for liver transplant.

Diabetes, Obesity Metabolism (DOM) NOW—April 2024

Kallistatin, also known as SERPIN A4, is a circulating protein with multiple effects in human body including anti-inflammatory and healing effects. Previous clinical studies in humans have shown that individuals who are overweight or those living with obesity produce less Kallistatin. The role of Kalistatin on glucose and energy metabolism in the setting of insulin resistance and type 2 diabetes as well as its potential as a therapeutic target however is currently unknown.

To investigate this further, mRNA expression of Kallistatin in human subcutaneous white adipose tissue (sWAT) was measured on 47 people before and after weight loss. Participants were derived from the clinical trial ‘Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)’. Effects of the protein on transgenic mice that systemically overexpress human Kallistatin and wild type littermate control mice under normal chow and high-fat diet conditions were also studied.

The study showed that the expression of Kallistatin in subcutaneous adipose tissue of people with obesity was increased after diet-induced weight loss. In the mice study, insulin excursions following glucose tolerance, markers of insulin resistance and hyperinsulinemic euglycemic clamp studies confirmed improved insulin sensitivity in mice overexpression the Kallsiatatin gene compared with wild-type mice. Improvement in insulin sensitivity was driven by reduced hepatic insulin resistance, and therefore, provides evidence for direct insulin sensitizing effects of Kallistatin for the first time.

This study suggests that Kallistatin has insulin-sensitizing effects in the liver, and its expression was increased following weight loss. This study provides a good basis to further investigate the function and regulation of this protein as a potential liver-specific target to enhance the beneficial effects of weight loss and potentially inducing long-term diabetes and obesity remission. The study was published in Molecular Metabolism.¹

GLP-1 therapy is widely used to treat type 2 diabetes and induce weight loss. Previous studies have also shown benefits of GLP-1 in reducing cardiovascular disease in obese/overweight people with¹ or without diabetes.² Early clinical studies also suggest benefits of GLP-1 therapy to reduce liver damage.³ To further explore the effectiveness of GLP-1 therapy to improve liver disease in people type 2 diabetes and chronic liver disease, researchers at the Karolinska Institutet undertook a register based study.

The study published in the journal Gut,⁴ used observational data from Swedish healthcare registers 2010–2020 to identify patients with chronic liver disease and type 2 diabetes. 10-year MALO risk (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or MALO-related death) was analyzed for initiators of GLP1 agonists versus non-initiators. The investigators found that among those who adhered to taking GLP-1 therapy, the risk of developing liver disease was halved (7.4%) compared with those not taking GLP-1 therapy (14.4%). The reduction in the risks of developing liver disease with GLP-1 therapy persists at 6 years with corresponding relative risk of 5.4% compared with 9.0% respectively. The study also showed that those who continued to take the drug for a long period of time had a lower risk of developing more severe forms of liver disease such as cirrhosis and liver cancer.

This study is based on retrospective data, and is therefore limited by various confounders. Nonetheless, evidence based on this work provided a basis for a larger study in a clinical trial setting to assess the efficacy of GLP-1 therapy to prevent liver disease progression in people with type 2 diabetes with chronic liver disease. This is important since there is currently no drug that is licenced for this indication. The research was mainly funded by Region Stockholm (CIMED), the Swedish Research Council and the Swedish Cancer Society.

Previous experimental study have shown that very low calorie Diet (VLCD)¹ can induced remission from type 2 diabetes by reduction in fat contents in the pancreas and in the liver. Since then, the DIRECT study has shown that remission from type 2 diabetes can be translated into clinical practice in selected patients.² In that study, which started in 2014 and ran for 2 years, 46% of people with type 2 diabetes who received the weight management programme were in remission 1 year later, and 36% at 2 years. Ongoing debate therefore persists regarding long-term efficacy of VLCD as means to induce long-term remission from type 2 diabetes.

Results from a three-year extension of the landmark DIRECT study published in Lancet Diabetes & Endocrinology³ have now shown that it is possible to stay in remission of type 2 diabetes for at least 5 years. However, the study also finds that maintaining weight loss and staying in remission can be challenging. This new study showed that 13% of people who had received the weight management programme and continued to have support through the extension study were in remission of type 2 diabetes at 5 years.

In this extension study, participants from the original DiRECT study were followed up for a further 3 years. Some participants from the original intervention group opted to continue to receive support and advice from their GP surgery to help them maintain weight loss over the next 3 years. Anyone who regained more than 2 kg during the 3 years was offered an additional package of support. This consisted of the low-calorie ‘soups and shakes’ diet for 4 weeks and support to reintroduce normal meals.

At year five, remission data was available for 93 people from the original control group and 118 people from the original intervention group (including the 85 people who had continued to receive support from their GP during years 3–5). The study showed that 12 out of 118 (10%) in the intervention group were still in remission at year five, compared to 5 out of 93 (5%) in the control group. In the intervention group, of the 85 who had continued to receive support from their GP, 11 (13%) were still in remission. At year five, the average weight loss in the intervention group was 5.6 kg compared with 4.6 kg in the control group. Weight loss was greater in the intervention group who continued to receive GP support—average weight loss of 6.1 kg but those who remained in remission had greater weight loss at 8.9 kg. Over the whole 5-year study period, people in the intervention group spent on average 27% of the time in remission compared to 4% in the control group. The intervention group also spent more time with their body weight lower than baseline, off blood sugar lowering medications and with blood sugar levels in the non-diabetes range than the control group.

The study therefore showed that while some people could stay in remis

Recurrent lockdowns and public health measures throughout the COVID-19 pandemic have restricted access to routine diabetes care, routine follow-ups and access to medications. These disruptions have resulted in adverse diabetes outcomes, but the true effects of the COVID-19 pandemic on long-term outcomes and mortality in people with diabetes are still unclear. A recent international study¹ commissioned by the World Health organization aimed to identify the impact of disruptions caused by COVID-19 on clinical outcomes in people with diabetes. This was a systematic review of the available literature and included 138 studies (n > 1 000 000 people). All studies compared pre-pandemic with pandemic periods. All-cause mortality (six studies) and diabetes-related mortality (13 studies) showed consistent increases, and most studies indicated increases in sight loss (six studies). One study found that, in 2021, there was an 11% rise in non-COVID-related deaths among people with diabetes compared with 2019.

In children and adolescents, most studies showed increases in diabetic ketoacidosis frequency or severity, some due to new-onset diabetes (69 studies). While there was a decrease in hospital admissions in adults, increases in diabetes-related admissions to paediatric intensive care units were reported (35 studies). The latter seemed to be very consistent across countries. No significant impact was noted for diabetic foot ulcer presentations (nine studies), emergency department admissions (nine studies) and overall amputation rates (20 studies). No studies investigated renal failure. The adverse impact appeared to be most pronounced for females, younger people and racial and ethnic minority groups. Findings from this study highlight the need to have a flexible and adaptable health care system to ensure maintenance of good clinical outcomes from people living with chronic disease like diabetes in the face of future epidemics. Recognizing and addressing disparities and inequalities in healthcare are crucial.