俄罗斯人民友谊大学，俄罗斯
DOI: 10.15761 / IOD.1000213
这封信总结了综述[1]的最新进展，特别提到了体重过重的2型糖尿病(T2DM)治疗的最新进展和前景。在伴有超重的T2DM病程早期，通常使用二甲双胍，以减少对胰岛素的需求，改善外周组织的敏感性，抑制肝脏葡萄糖的产生。二甲双胍不刺激胰腺β细胞分泌胰岛素，因此不会引起低血糖[2-8]。二甲双胍适用于治疗伴有肥胖的2型糖尿病，但对体重正常的患者也有效。二甲双胍的有益作用之一是抑制食欲，有助于减轻体重。然而，并不是所有的研究都证实长期服用二甲双胍后体重减轻;一些作者将二甲双胍在体重增加方面归类为中性[2,6,8]。二甲双胍使用的主要禁忌症是降低肾小球滤过率(GFR)，因为有乳酸酸中毒的风险。其他禁忌症包括与缺氧、代谢性酸中毒(饥饿)风险以及严重肝脏疾病相关的疾病[4]。如有二甲双胍禁忌症或其不耐受，则给予其他药物。 Sulfonylureas have been used for decades. Among their drawbacks is the risk of hypoglycemia, especially in aged patients with comorbidity, as well as the weight gain. A dysfunction of beta cells may occur after a prolonged stimulation by sulfonylureas [9]. The effect of glinides (e.g. repaglinide) is shorter than that of sulfonylureas. The action mechanism of both drug groups is similar, both contributing to the weight gain. Glinides are taken with meals and allow more liberal diets. Repaglinide can be used in conditions of renal insufficiency. The thiazolidinediones (e.g. pioglitazone) exhibit potent insulin-sensitizing properties. The intake of pioglitazone is accompanied by a low risk of hypoglycemia. Pioglitazone can be used in renal insufficiency. The drawback is a weight gain and retention of fluid, which is undesirable, in particular, in heart failure [4,10].
二肽基肽酶4 (DPP-4)抑制剂抑制胰高血糖素样肽1 (GLP-1)的降解，刺激胰岛素分泌，抑制胰高血糖素的合成。DPP-4抑制剂不会增加低血糖的风险，对体重没有影响。GLP-1受体激动剂的降糖作用比DPP-4抑制剂更明显。这些药物除了刺激胰岛素分泌外，还能减缓胃排空，抑制食欲，有助于减肥[9-11]。胃排空延迟可能与呕吐[12,13]和反流有关，这可能令人不安，特别是对于老年患者。据报道，Semaglutid是2013-2017年期间提出的抗糖尿病药物中最有效的;指出其在肥胖T2DM患者中的有效性[14,15]。有GLP-1受体激动剂影响β细胞增殖和减少凋亡的实验数据;然而，在人类中缺乏直接证据[11,16]。同时，也不排除GLP-1受体激动剂刺激导致β细胞衰竭的可能[17]。 A disadvantage is the delivery by injection as well as the relatively high price. An oral preparation of semaglutid is currently being evaluated. A combination of GLP-1 receptor agonists with metformin is efficient, associated with a low hypoglycemia risk and contributes to the weight loss [4].
肠道α -葡萄糖苷酶(阿卡波糖)抑制剂阻止碳水化合物的消化，降低餐后高血糖和继发性高胰岛素血症，同时不会引起低血糖。副作用包括流星和其他肠道症状[18]。一项meta分析表明，阿卡波糖对体重没有影响[19]，另一项meta分析表明，阿卡波糖对体重减轻有显著作用[20]，尤其是对伴有肥胖的T2DM患者[21]。在实验中，阿卡波糖降低了动物的体重[18]。
钠-葡萄糖共转运蛋白-2 (SGLT-2)抑制剂(格列净)抑制葡萄糖的肾脏重吸收并诱导与泌尿生殖系统感染风险相关的糖尿。渗透性利尿可以降低血压，从而降低心血管并发症的风险。糖尿伴热量损失可降低潜在的糖毒性，从而降低β细胞衰竭的风险[22]。SGLT-2抑制剂的作用机制与胰岛素无关，可与其他抗糖尿病药物及胰岛素联合使用[9,23,24]。特别是，有报道称SGLT-2抑制剂联合GLP-1受体激动剂对伴有肥胖的T2DM患者有利[25]。此外，应该指出SGLT-2抑制剂的生酮作用，因为从碳水化合物到脂质作为能量来源的转换，[26,27]。低碳水化合物-高脂肪饮食(LCHFD)也有类似的效果，碳水化合物含量≤50克/天的饮食被称为生酮饮食[28,29]。在这种饮食的影响下，从食物中摄取的葡萄糖不足以维持肝脏和肌肉中糖原的储存。这导致血液中的葡萄糖和胰岛素水平降低，糖原储存减少，脂肪酸燃烧产生酮。这些酮类随后被大脑和肌肉用作能量来源。 The literature shows that diet studies with LCHFD in patients with T2DM and obesity do induce favorable effects on weight loss, blood glucose and insulin. However, there is a lack of data supporting a long-term efficacy, safety and health benefits of LCHFD [28,29]. Further studies are obviously needed. The action mechanisms of both LCHFD and SGLT-2 inhibitors are analogous (decreased availability of glucose), so that their combination would be probably efficient for the purpose of weight loss. However, caution is needed because of the risk of euglycemic ketoacidosis developing rarely in the course of the treatment by SGLT-2 inhibitors (incidence <0.2% in canagliflozin studies) [22], more frequently in type 1 diabetes, e.g. after alcoholic excesses, surgeries or intercurrent illnesses [24-27,30]. A combination of SGLT-2 inhibitors with a strict LCHFD is regarded to be contraindicated [31]. Considering that a prolonged adherence to LCHFD is difficult for patients, the compliance being poor, a combination of LCHFD with SGLT-2 inhibitors might contribute to the catabolism of fat depots causing less discomfort by the same effect than a strict LCHFD alone. Such an experimental therapy would require a tight clinical control. Further studies are needed.
最重要的问题之一是药品的价格。根据俄罗斯2014年的估计，单药治疗的年度费用(括号中-根据2018年9月29日的课程转换为美元:1美元= 65.59卢布)如下:格列本脲- 1256(19.29)，二甲双胍- 4396(67.02)，吡格列酮- 6077(92.65)，西格列汀- 38,873(592.67)，利拉鲁tid - 149,504 (2279.37) [32];canagliflozin，根据https://medi.ru/instrukciya/invokana_6939/cena/(2018年9月29日)- 28000-49000(426-747美元)。人们并不总是清楚某些药物的优势在多大程度上证明了价格差异的合理性。这个问题与科学诚信、利益冲突和出版物的可靠性有关。对于科学文献的审稿人来说，似乎很明显，在过去几十年中，医学和生物学研究的某些领域的论证质量已经恶化。某些出版物系列在没有参考已发表的批评的情况下继续进行[33-35]。人们已经注意到，T2DM患者，尤其是老年患者有高剂量治疗的趋势[36,37]，这可能是出于经济动机。严格的血糖控制很难长期维持而不产生不良的副作用，而这种控制的益处并不总是明显的[38-40]。多语用症增加了风险，尤其是在老年患者中[10]。 On the contrary to some earlier studies, the large randomized clinical trials (ACCORD, ADVANCE, VADT) lasting 3.5-5.6 years have found that intensive glycemic control either has no impact on cardiovascular outcomes or even worsens them [7,41,42]. Admittedly, the intensive glycemic control improved some nephropathy-related outcomes in ADVANCE and slowed the progression of albuminuria in VADT [43,44]. However, given the relatively small number of cases with end-stage renal disease, the benefits were recommended to be interpreted with caution [43]. Apparently, intensive glucose control had minimal effects on hard microvascular complications (severe renal changes, decreased GFR, laser treatment, cataract extraction, vitrectomy, and new neuropathy) during a period of 5 to 6 years [44]. There is a well-founded opinion that the tight glycemic control may be beneficial in primary prevention of cardiovascular complications in younger T2DM patients, but in older patients with established or subclinical cardiovascular disease it is potentially deleterious [42].
对于超重的2型糖尿病患者，使用有助于减肥的药物是很重要的。除了广泛使用的二甲双胍外，还应提及以下药物类别。GLP-1受体激动剂刺激胰岛素分泌，减缓胃排空，有助于减肥。SGLT-2抑制剂减少肾脏葡萄糖重吸收，降低血压，有助于减轻体重。肠道α -葡萄糖苷酶(阿卡波糖)抑制剂对体重的类似影响有待观察;然而，它的效率取决于饮食中的碳水化合物含量。重要的是，后两种药物的降糖作用与刺激β细胞分泌胰岛素无关。众所周知，胰岛的分泌功能可因刺激而衰竭[45]。相反，使胰岛素分泌处于静止状态可防止β细胞衰竭[46]。一些抗糖尿病药物的有害作用可由过量胰岛素介导，而过量胰岛素本身也会导致体重增加[47,48]。 Conversely, the reduction of insulin hypersecretion is a method of weight loss [49]. An experimental blockade of hyperinsulinemia in mice prevents obesity [50]. This indicates that drugs acting without stimulation of the insulin secretion are preferable, other things being equal. In conclusion, the goals of glycemic control need to be individualized based on the age, prognosis, presence of macrovascular disease, and risk of hypoglycemia [42].
Katsunori Nonogaki
东北大学生物医学工程研究生院
给编辑的信
收稿日期:2018年10月1日
投稿日期:2018年10月10日
发布日期:2018年10月15日
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2型糖尿病合并超重的药物治疗新进展[j]。综合肥胖糖尿病4:DOI: 10.15761/IOD.1000213
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