KEYSTONE, Colorado (EGMN) – Most pediatric endocrinologists rely on metformin as the linchpin in treating new-onset type 2 diabetes in adolescents, adding insulin in those who present in poor glycemic control.
“This isn’t an evidence-based treatment algorithm. There aren’t any studies in kids to guide us. But this is the current practice among most pediatric endocrinologists who treat a lot of youths with type 2 diabetes,” Dr. Phil Zeitler said at a conference on management of diabetes in youth sponsored by the Children’s Diabetes Foundation at Denver.
Dr. Zeitler is study chair for the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY), an ongoing, large, multicenter, NIH-sponsored study.
For the new-onset type 2 diabetic teen who is nonketotic and in “reasonable” glycemic control, current practice among most specialists is to start metformin at 500 mg/day, along with initiating standard diabetes education with an added focus on the basics of lifestyle change and weight loss. The daily dose of metformin is to be increased by no more than 500 mg a week to a target of 2,000 mg/day. It’s crucial to titrate slowly to minimize the GI side effects and keep the patient on board with the treatment program.
“I tell my patients that I want them on 2,000 mg/day and I really don’t care how long it takes to get there. If they’re not feeling well after a week, they stay at that dose for the next week,” explained Dr. Zeitler, professor of pediatrics and clinical science at the University of Colorado, Denver, and medical director of the Children’s Hospital Clinical Translational Research Center.
He stressed that what constitutes “reasonable” glycemic control in a new-onset patient is an individual physician decision because there is no evidence to provide guidance. He personally often uses an HbA1c of about 9% as a cutoff. He knows of other pediatric endocrinologists who use 10%, and still others who use an HbA1c closer to 8% as their threshold for turning to insulin.
Insulin isn’t generally considered first-line therapy for type 2 diabetes in adults. However, teens have far fewer approved treatment options. Insulin is effective, it acts synergistically with oral metformin to reduce glucose toxicity, and it sends the adolescent a message that this is a disease to be taken seriously.
For these reasons, Dr. Zeitler recommended the following treatment strategy for a new-onset type 2 diabetic adolescent in poor glycemic control who has no acidosis: Start metformin and diabetes education as previously described, along with 15-30 U of basal insulin given at night or whenever family supervision is most likely in order to ensure adherence.
“These kids will not take that insulin on their own,” he continued.
Once glucose control is attained – as signified by an HbA1c below 6.5% – wean the patient off insulin as tolerated.
“I would argue that there is no evidence that weaning slowly is any more effective than weaning quickly in these patients. You might as well find out if the patient is going to be on metformin alone. Some of my colleagues take very long time periods to wean patients off insulin, but I don’t necessarily see the value of that. It’s going to promote weight gain just at the moment when you’re most likely to get some weight loss out of this child, in those first few months,” according to Dr. Zeitler.
If acidosis is present in a new-onset patient in poor glycemic control, start the patient on metformin and use insulin as in a type 1 diabetic patient until the acidosis is resolved, then wean the patient off insulin.
For patients who can’t maintain an HbA1c below 6.5% on full-dose metformin alone, he recommended adding once-daily insulin detemir or glargine, starting at 10-20 U/day. If the patient is unable to maintain the target HbA1c despite long-acting insulin at a dose of 1 U/kg of body weight and there is evidence of postprandial hyperglycemia, it’s time to consider adding short-acting insulin. But, there’s a caveat.
“Keep in mind that this is going to substantially increase the burden on these children and therefore you may, in fact, not get any benefit because they won’t do it. You need to have a good conversation with the family and figure out what’s going to work,” Dr. Zeitler said.
Metformin is the sole oral agent approved for use in pediatric type 2 diabetes. It is a drug that’s well studied in adults, safe, and now costs no more than generic oral sulfonylureas. Among its desirable qualities are that it induces weight loss, there is mild improvement in lipids, it improves hirsutism and menstrual irregularities, and it may improve hepatic steatosis. Lactic acidosis, once thought to be a serious problem with metformin, was absolved in a meta-analysis of some 40,000 patients. Nonetheless, the drug shouldn’t be used in adolescents who have substantial renal disease, are dehydrated, or are having a radiologic procedure.
Sulfonylureas are rarely used in kids because they cause weight gain and hypoglycemia is a much bigger problem than in adults.
“It may be [that] the balance of insulin resistance and beta-cell function is different in kids and adults. Kids actually have relatively well-maintained beta-cell function, so when you give them a secretagogue, they’re able to produce large amounts of insulin, leading to substantial hypoglycemia. I have not been able to effectively use a sulfonylurea in a kid without substantial hypoglycemia,” the physician continued.
The thiazolidinediones are well studied in adults, where they reduce HbA1c by about 1% and might prolong beta-cell function, a highly desirable attribute in a teenager who may be living with type 2 diabetes for another 50 years. But there are no published studies on thiazolidinediones for treatment of type 2 diabetes in youth, and the drugs have substantial side effects, especially weight gain.
“When you think about the issue of treating a teenage girl who’s obese and we tell her to lose weight and get more active – and ‘By the way, here, take this drug that’s going to cause you to gain weight’ – that’s a problem in terms of therapeutic alliance,” Dr. Zeitler observed.
The glucagon-like peptide-1 analogue exenatide is the subject of an ongoing clinical trial in pediatric type 2 diabetes. Exenatide slows gastric emptying, increases insulin secretion, and causes weight loss, but has the disadvantage of being administered by twice-daily injections before meals.
The dipeptidyl-peptidase–4 inhibitors sitagliptin and saxagliptin have actions similar to exenatide, but without the desirable weight-loss feature. However, they do have the advantage of oral administration. Pediatric trials are in the design phase, according to Dr. Zeitler.
Dr. Zeitler serves as an advisor to numerous pharmaceutical companies.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
科罗拉多州基斯通(EGMN)——大多数小儿内分泌科医生惯用二甲双胍作为治疗初发青少年2型糖尿病的基础药物，对于血糖控制不佳者另追加胰岛素治疗。
Phil Zeitler博士在一次由丹佛儿童糖尿病基金会主办的青少年糖尿病管理研讨会上说：“这并非循证治疗原则。对孩子进行的相关研究寥寥无几，所以我们缺乏相应的指导。但这是当前治疗众多青少年2型糖尿病患者的大多数小儿内分泌科医生的实践操作。”
Zeitler博士担任青少年2型糖尿病治疗选择研究(TODAY研究)的主席，这是美国国立卫生研究院(NIH)发起的一项大规模多中心研究，目前尚在进行中。
对于无酮症且血糖控制合理的初发青少年2型糖尿病的患者而言，大多数专家的常规治疗为开始二甲双胍治疗，剂量为500 mg/天，并结合标准的糖尿病教育，其中着重强调改进生活方式和减轻体重的基本问题。随后，逐渐增加二甲双胍的日剂量，每周增加的剂量不得超过500 mg，最终达到2,000 mg/天的目标。必须缓慢调整剂量，这非常关键，以便于将胃肠道副作用控制在最小并使患者遵从治疗计划。
“我告诉我的患者，我希望他们的二甲双胍日剂量为2,000 mg，我确实不介意他们经过多长时间才达到这一目标。如果他们1周后感觉不适，次周可维持此剂量。”科罗拉多大学丹佛校区儿科与临床科学系教授、儿童医院临床转化研究中心的医学主任 Zeitler博士解释说。
他强调指出，初发患者实现“合理的”血糖控制完全是医生个人的决策，因为没有任何指导性先例。他本人经常使用约9%的HbA1c作为一个临界值。他了解到其他小儿内分泌科医生中有些使用10%，还有些使用接近8%作为添加胰岛素治疗的阈值。
一般不考虑将胰岛素用于成人2型糖尿病的一线治疗。然而，青少年获准的治疗选择远远少于成人。胰岛素治疗有效，可以与二甲双胍口服药产生协同作用，减少葡萄糖毒性，这向青少年传递了一条信息：这是一种需慎重看待的病。
鉴于这些原因，Zeitler博士推荐对初发2型糖尿病、血糖控制不佳但无酸中毒的青少年患者施行以下治疗策略：开始二甲双胍治疗和糖尿病教育(如前文所述)，同时在夜间或有家人监督时给予15~30 U的基础胰岛素，以确保治疗依从性。
他继续说：“这些孩子不会自行应用胰岛素”。
一旦实现糖尿病控制——定义为HbA1c<6.5%——根据耐受情况，可逐渐撤出胰岛素治疗。
“我认为，尚无证据表明对这些患者缓慢撤出胰岛素比快速撤出更有效。你也会发现患者是否会进行二甲双胍单药治疗。我的同事中有部分人撤出胰岛素花费了相当长的时间，但我并未看到这样做就一定有益处。在那最初几个月中，这种做法将促使他增重，而就在这时候这个孩子可能正值减重的时候。” Zeitler博士说。
血糖控制不佳的初发糖尿病患者在出现酸中毒时开始二甲双胍治疗，同时应用胰岛素，直至消除酸中毒，然后撤出胰岛素治疗，用法与1型糖尿病患者相同。
对于行全量二甲双胍单药治疗无法将HbA1c维持在6.5%以下的患者，他建议追加每日1次地特胰岛素或甘精胰岛素治疗，开始剂量为10~20 U/天。若患者应用长效胰岛素(剂量为1 U/kg体重)治疗后，仍无法维持HbA1c的目标水平，且有餐后高血糖的征象，则应考虑追加短效胰岛素。但这有一个附加说明。
Zeitler博士说：“谨记，这将大大增加这些儿童的负担，因此你实际上可能得不到任何收益，因为他们不会这么做。你需要和这个家庭促膝而谈，探讨一下有效的做法”。
二甲双胍是获准用于治疗小儿2型糖尿病的惟一一种口服药。该药已在成人中得到充分的研究，安全性好，且费用也不高于通用名药磺酰脲类口服药。其优良品质包括：可促进体重减轻，轻度改善血脂，改善多毛症和月经不规律，并且可能会改善肝脏脂肪变性。乳酸酸中毒曾一度被视为二甲双胍的一个严重问题，但有一项涉及约40,000例患者的荟萃分析为该药洗脱了这一罪名。尽管如此，此药仍不宜用于有严重肾病、处于脱水状态或在进行放射学手术的青少年。
磺酰脲类药物可引起体重增加，而且低血糖对于孩子而言要比对成人更为棘手，故该药很少用于孩子。
“情况可能为，孩子中胰岛素抵抗与β细胞功能的平衡不同于成人。孩子们β细胞的功能维持的相对较好，因此你给他们服用促分泌素时，他们能够产生大量胰岛素，导致严重的低血糖。在将磺酰脲类药物有效地用于孩子且不会引起严重低血糖发生方面，我一直也未能实现。”
噻唑烷二酮类药物在成人中得到了充分的研究，成人使用该药后HbA1c可减少约1%，并可能延长β细胞的功能，这对要伴随2型糖尿病度过另外50年的青少年而言是一个不可多得的优良品质。但目前还没有已发表的探讨噻唑烷二酮类药物用于青少年2型糖尿病治疗的研究，这类药物会导致许多不良反应，特别是体重增加。
“你在考虑对肥胖少女治疗的问题时，我们告诉她要减重并多进行运动——“在此顺便提一下，你要服用这种会导致你体重增加的药物”——这是在治疗联盟方面出现的问题，Zeitler博士评论道。
胰高血糖素样肽-1类似物艾塞那肽是一项进行中的小儿2型糖尿病临床试验的试验药。艾塞那肽可延缓胃排空，增加胰岛素分泌，引起体重减轻，但其弊端是1日2次餐前注射用药。
二肽基肽酶-4(DPP-4)抑制剂西他列汀和沙格列汀的作用与艾塞那肽相近，但没有减轻体重的特质，不过他们具备口服用药的优点。小儿临床试验正处于设计阶段，Zeitler博士透露。
Zeitler博士担任许多制药公司的顾问。
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