SGLT2 inhibitors for the treatment of diabetes: a patent review (2013-2018)

Introduction: The sodium-glucose co-transporter 2 (SGLT2) is ascribed to target renal tubular glucose re-absorption, and its inhibition has been proved to induce glucosuria which improves the glycemic index. Accordingly, SGLT2 inhibitors have found to be the promising class of antidiabetic agents for the management of type 2 diabetes mellitus. A large number of SGLT2 inhibitors have developed through structural modification and investigated for their ability to selectivity inhibit SGLT2 transporters with better bioavailability.

Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.

Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted.     

The comparative effects of metabolic surgery,SGLT2i,or GLP-1RA in patients with obesity and type 2 diabetes: a retrospective cohort study

BackgroundNew antidiabetic agents (sodium-glucose cotransporter-2 inhibitor [SGLT2i] and glucagon-like peptide-1 receptor agonist [GLP-1RA]) and metabolic surgery have protective effects on metabolic syndromes.ObjectivesTo compare the changes of metabolic parameters and costs among patients with obesity and type 2 diabetes undergoing metabolic surgery and initiating new antidiabetic agents over 12 months.SettingHong Kong Hospital Authority database from 2006–2017.MethodsThis is a population-wide retrospective cohort study consisting of 2616 patients (1810 SGLT2i, 528 GLP-1RA, 278 metabolic surgery). Inverse probability treatment weighting of propensity score was applied to balance baseline covariates of patients with obesity and type 2 diabetes who underwent metabolic surgery, or initiated SGLT2i or GLP-1RA. Metabolic parameters and direct medical costs were measured and compared from baseline to 12 months in metabolic surgery, SGLT2i, and GLP-1RA groups.ResultsPatients in all 3 groups had improved metabolic parameters over a 12-month period. Patients with metabolic surgery achieved significantly better outcomes in BMI (?5.39, ?.56, ?.40 kg/m², P < .001), % total weight loss (15.16%, 1.34%, 1.63%, P < .001), systolic (?2.21, ?.59, 1.28 mm Hg, P < .001) and diastolic (?1.16, .50, ?.13 mm Hg, P < .001) blood pressure, HbA1c (?1.80%, ?.77%, ?.80%, P < .001), triglycerides (?.64, ?.11, ?.09 mmol/L, P < .001), and estimated glomerular filtration rate (3.08, ?1.37, ?.41 mL/min/1.73m², P < .001) after 12 months compared with patients with SGLT2i and GLP1-RA. Although the metabolic surgery group incurred the greatest direct medical costs (US$33,551, US$10,945, US$10,627, P < .001), largely due to the surgery itself and related hospitalization, the total monthly direct medical expenditure of metabolic surgery group became lower than that of SGLT2i and GLP-1RA groups at 7 months.ConclusionBeneficial weight loss and metabolic outcomes at 12 months were observed in all 3 groups, among which the metabolic surgery group showed the most remarkable effects but incurred the greatest medical costs. However, studies with a longer follow-up period are warranted to show long-term outcomes.     

Therapeutic traditions in type 2 diabetes — are they changing?

The utilisation of antidiabetic drugs reflects both the prevalence of diabetes and the different therapeutic traditions of physicians. A questionnaire survey to study attitudes to the use of oral antidiabetic drugs amongst physicians and possible changes in treatment habits was carried out in a representative sample of Finnish physicians (n=454) in 1992 and the results were compared with those of a similar survey carried out in 1985, and with drug utilisation statistics.The mean fasting blood glucose level at which a physician would start pharmacological treatment was 8.7 mmol·l^–1, which was significantly lower than in the 1985 survey. The responses to various case histories suggested a more active approach to pharmacological treatment compared to the 1985 survey. Insulin treatment especially seems to have gained in popularity. This change in attitude was paralled by an increase in the consumption of antidiabetic drugs in Finland during the observation period. The increase in use of oral drugs was steeper in Finland than in Norway and Sweden.Whether this active approach will improve the metabolic control and prognosis of patients with Type 2 diabetes, remains to be demonstrated.     

槲皮素的结构修饰及生物活性研究进展

槲皮素是蔬菜、水果、中药中常见的黄酮类化合物,是天然的抗氧化剂,具有抗癌、抗糖尿病、抗菌、抗炎、抗病毒等生物活性。由于槲皮素生物利用度低,限制了其在临床上的应用。通过各种方法设计和合成新的槲皮素衍生物,以改善其缺点,进而发挥预防和治疗疾病的作用。通过对槲皮素衍生物的合成及其抗癌、抗糖尿病、抗炎、抗菌和抗病毒活性进行综述,并对其构效关系进行分析,为天然化合物的开发和利用奠定基础。     

Hypoglycaemic effects of the novel antidiabetic agent repaglinide in rats and dogs

1. Repaglinide, a novel compound with a nonsulphonylurea structure, is currently being clinically tested as a therapeutic agent. In the present study, the hypoglycaemic effects of repaglinide in rats and dogs were investigated.
2. Whereas the R-enantiomer, AG-EE 624 ZW, showed only weak hypoglycaemic activity, the S-enantiomer, repaglinide, turned out to be a potent hypoglycaemic compound in rats after oral as well as after intravenous administration. Only 50% of the dose of repaglinide was needed to be equieffective with the racemic mixture AG-EE 388 ZW. The corresponding ED₅₀ values calculated for the effects after 120 min p.a. (intravenous administration) were 3.4 μg kg⁻¹ (repaglinide) and 6 μg kg⁻¹ (AG-EE 388 ZW).
3. When compared to glimepiride or glibenclamide, repaglinide displayed a 18 to 25 times higher potency in fasted rats. The ED₅₀ values calculated for the effects after 120 min p.a. (oral administration) were 10 μg kg⁻¹ (repaglinide), 182 μg kg⁻¹ (glimepiride) and 255 μg kg⁻¹ (glibenclamide).
4. In glucose loaded rats (0.5, 1.0, 2.0 and 3.0 g kg⁻¹ glucose, p.o.) repaglinide exerted a very strong antihyperglycaemic activity which was even more pronounced than under normoglycaemic conditions. So for a reduction in blood glucose of 1 mmol l⁻¹, 10.3, 9.3, 7.0 8.4 and 7.2 μg kg⁻¹ repaglinide were needed after glucose loads of 0.0, 0.5, 1.0, 2.0 and 3.0 g kg⁻¹, respectively.
5. In beagle dogs repaglinide again showed a pronounced hypoglycaemic effect (ED₅₀ 28.3 μg kg⁻¹) which lasted for up to 24 h. However, insulin levels were only transiently increased.
6. The in vivo data presented are well supported by recently published in vitro findings. From its activity profile, repaglinide appears to be a promising new therapeutic agent.

     

2000年～2002年重庆市18家医院抗糖尿病药物应用分析

目的 :对2000年～2002年重庆市18家医院抗糖尿病药物的用药现状和趋势做出客观评估。方法 :调查重庆市18家医院2000年～2002年应用抗糖尿病药物的主要品种、金额等 ,分析临床用药情况。结果 :抗糖尿病药物金额2000年、2001年、2002年分别为498、643、649万元 ,年平均增长率为15 03 %。胰岛素注射液占据38 56 %的市场份额 ,其中混合胰岛素注射液占整个胰岛素注射液59 02 %的市场份额。结论 :抗糖尿病药物是一类很有发展潜力的药物 ,混合胰岛素和新型口服抗糖尿病药物的用量将不断增加。     

2000年～2002年同济医院降糖药应用分析

目的 :分析降血糖药在同济医院的应用情况。方法 :调查同济医院 2 0 0 0年～ 2 0 0 2年该类药物的用量、品种 ,计算金额、DDDs。结果 :降糖药近 3年来总的用量在上升 ,品种增加 ,其中磺酰脲类药物的使用金额和DDDs总值均列第 1。结论 :降糖药的用药价格水平正逐步上升 ,是一类有发展前途的药物     

老年糖尿病人群低血糖风险和抗高血压药物应用的队列研究

目的 了解抗高血压药物应用与服用抗糖尿病(DM)药物治疗的老年DM人群低血糖风险的方法。方法 根据老年DM人群药物使用调查问卷，从我们建立的上海市社区老年DM人群用药监测系统中选取2001年6月至2002年6月服用抗DM药物的老年DM合并高血压者进行回顾性队列研究；以经过医院明确诊断的低血糖事件为观察终点；抗高血压药物相关的低血糖风险用经过校正的相对危险度(RR)表示；采用多个协变量的Poisson回归模型，在控制可能的混杂因素作用的基础上，对RR值进行估计。结果 观察期1a内确诊发生低血糖34例，同时服用抗高血压药物者低血糖发生率(2．76％)高于未服用抗高血压药物者(1．51％)，但经可能的混杂因素校正后，两者差异无显著性[RR=1．98，95％可信区间(CI)0．59～ 6．59]；复方降压片与其他抗高血压药物联合应用可显著增加同时服用磺酰脲类抗DM药物的老年患者低血糖的危险性(RR=6．87；95％ CI，1．01～47．21)；钙拮抗剂、利尿剂、选择性β受体阻滞剂、ACE抑制剂并不增加老年DM患者低血糖风险(P＞0．05)；但其中ACE抑制剂单一用药在抗高血压药物中低血糖发生率最高(4．91％)，对老年DM患者应慎用。结论在老年DM合并高血压的人群中，传统制剂复方降压片可以增加服用磺酰脲降糖药的老年患者的低血糖风险；对于老年DM患者抗高血压药物的选择极为重要，除考虑降压药物本身的疗效外，还应注意降压药对老年DM代谢控制的影响。     

液相色谱-质谱联用法检测中药降糖制剂中非法掺入的苯乙双胍和格列本脲

目的建立检测中药降糖制剂中非法掺入的苯乙双胍和格列本脲专属性方法 ,并对若干市售药品进行检测。方法采用液相色谱 离子阱质谱联用法。选用DiamonsilC18柱 ,以乙腈 水 甲酸(V∶V∶V =6 0 0∶4 0 0∶0 1)为流动相 ,对中药降糖制剂的提取液进行液相色谱 离子阱质谱分析。通过与对照品的色谱及质谱行为相比较 ,对中药降糖制剂中非法掺入的合成降糖药进行定性鉴别。结果在 4种受试中药降糖制剂中 ,2种被检测到同时掺有苯乙双胍和格列本脲 ,1种被检测到掺有格列本脲。结论该方法选择性强 ,灵敏度高 ,可作为分析检测非法中药降糖制剂的有效方法