Type 2 diabetes remission associated with reduction of CVD and CKD complications, study finds

16th February 2024

Patients who successfully reversed a type 2 diabetes diagnosis though lifestyle changes substantially reduced their cardiovascular disease (CVD) and chronic kidney disease (CKD) risk in the long term, a study has found.

Published in the journal Diabetologia, the results came from a large trial of almost 4,500 participants in which doctors were comparing an intensive lifestyle programme with standard diabetes education and support.

Taking no diabetes medications and having a HbA1c of less than 48 mmol/mol (6.5%) at a single point in time was classed as remission.

Overall, those who achieved remission through the lifestyle changes – in whichever group – had a 33% lower rate of CKD and a 40% lower rate of CVD.

But those who had the most intensive support were more likely to be in remission from their diabetes, with 12% meeting the criteria at least one follow-up and falling to 7% over time compared with around 2% in the regular support group.

Being in remission overall was significantly linked to changes in weight and risk factors over the years, the study found.

Average weight loss associated with remission was 7.3kg after one year and 4.5kg after four years.

There were also significantly greater improvements in HDL-cholesterol and fitness after one and four years, and significantly greater systolic blood pressure improvements after one year among participants with remission compared with those without remission, the team said.

The analysis also showed systolic blood pressure decreased more and HDL-cholesterol increased more among participants who achieved a greater duration of diabetes remission.

There was a dose-response relationship with those who had remission for at least four visits seeing the most impact, the researchers said.

Those taking part in the study – which ran between 2001 and 2016 – had a mean age of 59 years and on average were in the range of severe obesity.

It was noted that while 18% of participants achieved remission at some point during follow-up, the percentage of participants with current remission had decreased to 3% by the eighth year of the study.

The figures underline, the challenges of keeping weight off using lifestyle interventions, the researchers said.

But for those with at least four years of remission the risk of CKD and CVD was reduced by 55% and 49% respectively.

The analysis also noted participants with a short duration of diabetes, low starting HbA1c and a large magnitude of weight loss were most likely to experience remission.

Study lead Professor Edward Gregg, head of the School of Population Health, RCSI University of Medicine and Health Sciences in Dublin, said: ‘As the first intervention study to associate remission with reduction of diabetes-related complications, this is encouraging news for those who can achieve remission from type 2 diabetes.

‘While our study is also a reminder that maintenance of weight loss and remission is difficult, our findings suggests any success with remission is associated with later health benefits.’

Another recent study has found that regular bouts of moderate to vigorous physical activity can protect patients with type 2 diabetes from developing kidney disease.

A version of this article was originally published by our sister publication Pulse.

Persistent CD19 CAR T-cells may explain longer remission for children with relapsed leukaemia

7th July 2023

The presence of persistent CD19 CAR T-cells may account for why some children with relapsed-refractory acute lymphoblastic leukaemia have longer remission, according to a study by a team of UK researchers.

The use of CAR T-cells that target CD19 is an effective therapy for relapsed and refractory acute lymphoblastic leukaemia in children. In fact, the therapy is now a widely used therapeutic approach for relapsed or refractory lymphomas.

The effectiveness of CAR T-cell therapy requires that these modified T-cells persist within the body. But what enables these cells to persist was the question posed in a recent study published in the journal Nature Medicine.

The team of UK researchers systematically analysed CD19 CAR T-cells of 10 children who had either relapsed or refractory acute lymphoblastic leukaemia (B-ALL) enrolled in the CARPALL study. The researchers then studied molecular features and clonal dynamics of CAR T-cells in this CARPALL study up to five years after infusion.

Leukaemia remission improved

The team studied 15 consecutive patients with high-risk or relapsed CD19 positive B-ALL treated with CAR T-cell therapy using cells isolated from cryopreserved samples of blood or bone marrow. From this cohort, 13 had achieved complete remission and six had subsequently relapsed. However, the remaining seven achieved long-lived remissions maintained by detectable CAR T-cells and concomitant B cell aplasia.

The researchers analysed a total of 264,827 single cells, approximately 50,000 of which were CAR T-cells. The long-lived CAR T-cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. In addition, the signature was dominant among circulating CAR T-cells in those children with a long-lived treatment response.

Investigating further, the researchers found that this same signature was present across T-cell subsets and clonotypes, indicating that persisting CAR T-cells converge transcriptionally. They also found the signature in two adult patients who had previously been given a different CD19 CAR T-cell product for chronic lymphocytic leukaemia and had a decade-long remission.

An important finding from the study was how this persistent transcriptional signature was reproducible across thousands of cells in every patient with long-lived CAR T-cells and durable anti-B-ALL responses. These findings suggest that this persistence signature might be specific to long-lived CAR T-cells and raises the possibility of a universal transcriptional signature indicative of clinically effective, persistent CD19 CAR T-cells.

Peanut oral immunotherapy increases desensitisation and remission in children

27th January 2022

Peanut oral immunotherapy in children has been shown in a randomised, placebo trial to increase rates of both desensitisation and remission

The use of peanut oral immunotherapy in children is associated with an increase in the proportion who achieve desensitisation and remission. This was the conclusion of a randomised, placebo-controlled trial by researchers from the Department of Paediatrics, Arkansas, USA.

Peanut allergy (PA) currently affects approximately 2% of the general population and commonly affects children as revealed in one study which how among 3218 children identified with food allergy, 24.8% reported a peanut allergy. Although allergy avoidance is the best strategy, in recent years, peanut oral immunotherapy has become more widely available and one product, Palforzia has been approved for use in the EU. Trial data shows that oral immunotherapy with Palforzia (known as AR101 in the study) in children and adolescents results in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at an exit food challenge compared to placebo. Nevertheless, whether use of oral immunotherapy can induce both desensitisation (i.e., a higher allergic reaction threshold) and remission, in other words, non-responsiveness after discontinuing therapy, is unclear.

For the present study, the US team undertook a randomised, placebo trial in children aged 12 years and younger and who were found to react to 500 mg or less or peanut protein, during a double-blind, placebo-controlled food challenge (DBPCFC). They randomised children 2:1 to peanut oral immunotherapy or placebo for a total of 134 weeks and which was equivalent to giving 2000 mg of peanut protein per day. This was followed by 26 weeks of no treatment and then re-assessment at week 160. The DBPCFC used a dose of 500 mg of peanut protein at week 134 and at week 160. At week 134, those who passed the DBPCFC challenge were considered to be desensitised and those who passed the challenge at week 160, deemed to be in remission. The primary endpoint was the proportion of children desensitised after 134 weeks of oral immunotherapy and the main secondary outcome was the proportion who were defined as in remission at week 160.

Findings

A total of 146 participants with a median age of 39.3 months (32% girls) were enrolled and 96 assigned to peanut oral immunotherapy.

At week 134, 71% of those receiving oral immunotherapy and 2% of those given placebo, met the primary outcome of desensitisation (risk difference, RD = 69%, 95% CI 59 – 79, p < 0.0001). The median tolerated peanut protein dose was 5005 mg (roughly 16 peanuts) for those given immunotherapy compared to 5 mg in the placebo group (p < 0.0001).

After discontinuation of immunotherapy, 21% of those previously receiving treatment and 2% of the placebo group, met the remission criteria (RD = 19%, 95% CI 10 – 28%, p = 0.0021) at week 160, although the tolerated dose of protein was lower at 755 mg for those who had immunotherapy but 0 mg for the placebo arm.

The authors concluded that peanut oral immunotherapy before age 4 increased both desensitisation and remission and called for future studies to focus on aged-defined benefits and risk to define the most appropriate window of opportunity to induce remission.

Citation

Jones SM et al. Efficacy and safety of oral immunotherapy in children aged 1 to 3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study Lancet 2022

Monitoring adalimumab levels valuable for assessing remission in children with Crohn’s disease

9th June 2021

Adalimumab is effective for children with Crohn’s disease but little is known about the impact of therapeutic monitoring on clinical outcomes.

The clinical symptoms of Crohn’s disease (CD) are similar in adults and children although there is evidence that cases of paediatric CD are on the rise, with one study estimating that the highest incidence, at 23 per 100,000 person-years occurred in Europe.

Endoscopic evidence of mucosal healing is a valuable therapeutic goal that decreases the risk of disease relapse although little is known about the association between mucosal healing and therapeutic levels of biological treatments such as adalimumab.

This prompted a team from the Department of Paediatrics, Samsung Medical Centre, Korea, to examine the relationship between therapeutic drug monitoring of adalimumab and mucosal healing and clinical remission in paediatric patients with CD.

The team prospectively recruited paediatric patients with CD receiving adalimumab maintenance therapy and who underwent routine endoscopic evaluation of mucosal healing and therapeutic drug monitoring. Monitoring assessments were made at four months and then at years one, two and three.

Findings

In total, 31 children with a mean age of 14.8 years (74% male) were included in the analysis. After one year of treatment, 26 (83.9%) had achieved clinical remission and 17 (54.8%) had complete mucosal healing.

The mean adalimumab trough levels were higher in patients who had achieved remission compared to those with active disease (7.6 mcg/ml vs 5.1 mcg/ml, remission vs active disease).

Similarly, trough levels of adalimumab were significantly higher in those who achieved mucosal healing after one year (14.2 mcg/ml vs 7.8mcg/ml, mucosal healing vs non-healed, p = 0.03).

Although only 23 children were evaluated after 3 years, adalimumab trough levels remained above 10 mcg/ml and a similar proportion of children maintained mucosal healing (64.3%) and clinical remission (92.9%).

Using receiver operating curves, authors calculated that the optimal cut-off adalimumab trough levels to achieve mucosal healing was 8.18 mcg/ml.

In discussing their findings, the authors commented on the results demonstrated that mucosal healing rates increased when adalimumab was used over the longer term and that the drug maintained its efficacy.

They concluded that there was merit in using therapeutic drug monitoring to guide proactive optimisation of drug levels to achieve the goal of mucosal healing.

Citation
Kim MJ et al. Therapeutic Drug Monitoring of Adalimumab During Long-term Follow-up in Paediatric Patients with Crohn Disease. JPGN 2021;72:870-6.