Update: Pediatric Diabetes

1 LIRAGLUTIDE (A GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONIST) NOW APPROVED FOR ADOLESCENTS WITH TYPE 2 DIABETES

Despite the marked rise in incidence of type 2 diabetes (T2D) in adolescents and young adults, metformin remained the only US Food and Drug Administration (FDA) approved oral medication for treatment of early disease in this population. Multiple groups of medications are available for adults with T2D. Loss of glycemic control has been a major drawback with metformin monotherapy which eventually requires addition of insulin. For the first time in July 2019, the FDA approved the glucagon-like peptide 1 (GLP-1) receptor agonist, liraglutide, for pediatric use.

A study published in the New England Journal of Medicine in their August 2019 edition titled “Liraglutide in Children and Adolescents with Type 2 Diabetes” laid the foundation for this FDA recognition.1 The Evaluation of Liraglutide in Pediatrics with Diabetes (Ellipse) phase 3 randomized control trial was conducted at 84 sites in 25 countries from 2012 to 2018. The aim of the study was to assess the superiority of liraglutide compared to placebo when added to metformin therapy with or without insulin use in adolescents with T2D between 10 and 17 years of age. Patients were randomly assigned to receive subcutaneous liraglutide (up to 1.8 mg per day) (n = 66) or placebo (n = 68) for a 26-week double-blind period in a 1:1 ratio, followed by a 26-week open-label extension period.

At the 26-week initial analysis of the primary efficacy end point, the mean glycosylated hemoglobin level had decreased significantly by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo (P < .001); the difference increased to −1.30 percentage points by 52 weeks indicating the superiority of liraglutide to placebo. The fasting plasma glucose level had decreased at both time points in the liraglutide group but had increased in the placebo group. The most common adverse effects associated with liraglutide in this trial were mild gastrointestinal complaints.

Interestingly, despite an improvement in the diabetes profile, this study did not see a significant change in the body mass index (BMI) between the two groups. They attribute this to the possibility of children continuing to grow as well as the small sample size.

GLP-1 receptor agonists have been in use in adults since 2005 and have shown effectiveness in improving glycemic control and having cardioprotective ability. They also help with weight reduction in adults. In August 2019, a review was published on the first oral GLP-1 agonist, semaglutide, in Diabetes Technology & Therapeutics.2 We hope that more studies are performed on pediatric T2D populations to help them achieve better glycemic control. We owe our patients more medication options than just metformin and insulin.

This makes the Ellipse trial so important, and liraglutide in conjunction with metformin (with or without insulin) is a good additional option for adolescents with T2D.

2 SERUM URIC ACID ELEVATION—A NOVEL BIOMARKER FOR T2D-RELATED COMORBIDITIES?

Serum uric acid (SUA) elevation is increasingly recognized as an important risk factor for development of hypertension and renal disease in adults with type 1 diabetes (T1D) and T2D.3 The mechanisms by which elevated SUA confers increased risk for these vascular pathologies are incompletely defined but attributed to various factors such as inflammation, insulin resistance (IR), intrarenal hemodynamic dysfunction, vascular, glomerular, and tubular injuries, and loss of nephron mass.

Longitudinal data on the relationship between SUA and hypertension or elevated urinary albumin excretion (UAE) in adolescents with T2D are lacking. This relationship was described recently in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study by Bjornstad et al.4 The authors hypothesized that elevated SUA predicted development of elevated UAE and hypertension in adolescents with T2D.

This study was conducted in 539 obese youth, aged 12 to 17 years, with T2D duration <2 years. The study evaluated the relationship between SUA and outcome variables longitudinally over an average follow-up of 5.7 years, adjusting for age, sex, race/ethnicity, BMI, glomerular filtration rate, angiotensin converting enzyme inhibitor/angiotensin receptor blocker use, and TODAY treatment group assignment. Hyperuricemia (>6.8 mg/dL) was present in 25.6% of participants, hypertension in 18.7%, and elevated UAE in 6.1%. During follow-up of up to 7 years, hypertension developed in 37.4% and UAE in 18.0%. Higher baseline SUA increased the risk of incident hypertension (hazard ratio [HR] 1.19; 95% CI, 1.03-1.38, per 1 mg/dL increase in SUA) and elevated UAE (HR 1.24; 95% CI, 1.03-1.48) in adjusted models.

This study shows that hyperuricemia was present in a quarter of youth with T2D. Higher baseline SUA conferred an increased risk for onset of hypertension and elevated UAE. SUA could be a potential marker to be used for screening in identifying youth with T2D at risk for hypertension and renal disease. Further studies would be needed to explore the relationship between lowering SUA and its effect on the development of diabetes-related renal disease and cardiovascular disease.

3 CAN MINDFULNESS HELP ADOLESCENTS AT RISK FOR T2D?

Mindfulness-based interventions (MBIs) have been shown to have beneficial effects in patients with various chronic medical conditions. Adults with T1D and T2D were shown to have reduced rates of anxiety and depression using MBIs.5

Depression symptoms are associated with greater IR in adolescents, predict worsening IR over time, and relate to T2D onset in young adulthood.6 Depression is hypothesized to affect IR through hypercortisolism and stress-related behavior such as emotional eating.

A recent randomized controlled trial by Shomaker et al explored the effect of brief MBIs and their relationship to sustained improved clinical outcomes in adolescents at risk for T2D.7

This study is a single-center study that was conducted in adolescent girls between 12 and 17 years of age who were overweight or obese (BMI > 85%) with family history of T2D and depressive symptoms (total score ≥ 16 on the Center for Epidemiologic Studies Depression Scale).

Participants were randomized to receive six sessions of either MBI or cognitive behavioral therapy (CBT). At baseline and 1 year, mindfulness, depression, IR, and body composition were assessed with validated instruments. A total of 71% of patients in the MBI and 81% in the CBT group had retention at the end of 1 year. At the 1-year mark, although depression scores decreased significantly in both the mindfulness and CBT group, the change was more in the MBI group (P = .03). IR decreased significantly (P < .01) in adolescents randomized to MBI compared to those in CBT.

Thus, MBI may be uniquely suited for adolescents at risk for T2D by affecting components such as sleep, physical activity, eating behavior, and stress arousal. However, this is a smaller pilot study and would need further exploration using larger studies. Research into defining the mechanisms in which MBIs work would also be beneficial in developing integrative models for this population group.

CONFLICT OF INTEREST

The authors have no known conflicts of interest.

1、利拉鲁肽 (胰高血糖素样肽1受体激动剂) 现已批准用于青少年2型糖尿病患者

尽管2型糖尿病在青少年与年轻人中发病率明显升高, FDA批准的针对这个群体的药物依然只有二甲双胍, 直到2019年七月, 胰高血糖素样肽-1(GLP-1)受体激动剂的应用批准打破了这个僵局。

2019年8月<<新英格兰医学杂志>>发表了一项题为: 利拉鲁肽在儿童和青少年2型糖尿病中的应用的研究,为FDA的批准提供了基础。这项研究利拉鲁肽在儿童糖尿病中作用(Ellipse)的临床3期随机对照试验从2012至2018年在25个国家的84个地区进行, 以评估在10-17岁的人群中, 二甲双胍联合利拉鲁肽与否的治疗效果。病人被随机分为接受皮下利拉鲁肽治疗组(不多于1.8mg每天, n=66)和安慰剂组(n=68), 以1:1的比例进行为期26周的双盲随机试验, 以及随后26周的开放标签延长试验。

在26周之后的初始分析中, 利拉鲁肽组的平均糖化血红蛋白降低了0.64% , 而安慰剂则上升了0.42%, 在52周后其差异增加到1.3%, 表明利拉鲁肽优于安慰剂。

Ellipse试验结果非常重要, 利拉鲁肽和二甲双胍联用(有或无胰岛素)对青少年糖尿病是一个额外的好的方案。

2、血清尿酸升高是一种新的2型糖尿病相关疾病标志物?

血清尿酸(SUA)升高被认为是糖尿病患者高血压和肾脏病的重要危险因素。但是升高的SUA增加心血管疾病风险的机制并不完全清楚, 可能与多个因素有关, 包括炎症、肾内血流动力学障碍、血管、肾小球和肾小管损伤以及肾单位质量损失。

青少年2型糖尿病人群中SUA与高血压或尿白蛋白排泄(UAE)增加之间关系的纵向数据缺乏。Bjornstad等人最近在青少年2型糖尿病治疗方案(TODAY)研究中描述了这种关系。作者假设升高的SUA能够预测青少年2型糖尿病UAE的升高和高血压的发展。

近期一份针对青少年2型糖尿病的研究探讨了这个问题。该研究纳入了539名12-17岁2型糖尿病病程<2年的肥胖青年, 评估了血清尿酸和各种糖尿病并发症的关系, 平均随访5.7年, 并且校正了年龄、性别、种族、BMI、肾小球滤过率、血管紧张素受体拮抗剂使用, 以及试验治疗分组。25.6%的参与者有高尿酸血症(>6.8 mg/dL), 18.7%有高血压, 6.1%有UAE的升高。 随访7年, 发现高血压发生率为37.4%, UAE发生率为18.0%。在校正后的模型中, 较高的基线SUA增加了发生高血压(危险比[HR]1.19; 95%CI, 1.03-1.38, SUA每增加1 mg/dL)和蛋白尿升高(HR 1.24; 95%CI, 1.03-1.48)的风险。

这项研究表明, 四分之一患有2型糖尿病的年轻人存在高尿酸血症。基线血尿酸越高, 发生高血压和尿白蛋白升高的风险越高。血清尿酸可作为筛查2型糖尿病青少年患有高血压病和肾脏病的潜在标记物。未来需要更深入的研究来探讨降低SUA与糖尿病相关肾病和心血管疾病的关系。

3、用心关注(mindfulness)是否对有2型糖尿病风险的青少年有帮助?

基于用心关注的干预(Mindfulness-based interventions, MBIs)已经证实对于各种慢性疾病的患者有有益效果, 1型和2型糖尿病成人的抑郁和焦虑发病率都显示降低。

一项随机对照研究探索了这个问题。这是一单中心研究, 入选12-17岁的超重或肥胖青春期女孩(BMI >85%), 均有2型糖尿病家族史并有抑郁症状(在抑郁症流行病学中心的总评分≥16)。

参与者被随机安排接受6次MBIs, 或者认知疗法治疗(cognitive behavioral therapy, CBT)。在基线及1年后评估抑郁、胰岛素抵抗及身体指标。MBIs组71%的参与者和CBT组81%的参与者一直治疗至1年结束。结果发现MBIs组和CBT组抑郁评分都显著下降, MBIs组下降得更为显著(P=0.03), 同时, 其胰岛素抵抗也显著下降(P<0.01)。

研究者认为, MBIs可能通过影响睡眠、体育活动、进食行为和压力唤醒等因素, 特别适合2型糖尿病的高危青少年。然而, 这只是一个较小的先导性研究, 需要利用更大规模的研究, 进行进一步的探索。MBIs的相关机制研究也能为探索这一人群的综合模型提供思路。