Oral antidiabetic agents as cardiovascular drugs

The increased risk of cardiovascular disease associated with type 2 diabetes is well documented. Lesser degrees of abnormal glucose metabolism including impaired fasting glycaemia and impaired glucose tolerance are also associated with increased cardiovascular risk. Studies showing improved cardiovascular outcomes with oral antidiabetic agents are limited, with the UKPDS demonstrating improved macrovascular outcomes only in a subgroup of obese patients with type 2 diabetes treated with metformin, and the heavily criticized STOP NIDDM trial showing a reduction in the number of cardiovascular events with the alpha glucosidase inhibitor acarbose. In recent years there has been an increase in the number of oral antidiabetic drugs available to treat the hyperglycaemia of diabetes. Some of these drugs have complex metabolic properties, additional to their antihyperglycaemic effect, improving endothelial function and markers of atherogenesis, with the potential to reduce cardiovascular morbidity and mortality, as supported by the recently published results of the PROACTIVE study. The results of further long-term cardiovascular outcome studies with these newer agents are awaited.     

New oral antidiabetic agents

The pathophysiology of hyperglycemia in type 2 diabetes (T2DM) involves 3 main defects: insulin deficiency, excess hepatic glucose output, and insulin resistance. Oral anti-diabetic agents act in a variety of ways. These include agents that stimulate insulin secretion, reduce hepatic glucose production, delay digestion and absorption of intestinal carbohydrate or improve insulin action. Because of improved knowledge of pathophysiology, new drugs with mechanisms of action focussed on specific pathophysiological alterations have appeared, in order to utilize all the possibilities of treating this condition. Here, we focus on the new agents used in the latest years and the overcoming ones in future, in particular incretin-based therapies, drugs inhibiting kidney glucose reabsorption (SGLT2 inhibitors), and glucokinase activators. The strategy for new drug development advocated here is to establish a broad range of anti-diabetic medicines with different mechanisms of action and potential opportunities for effective combination therapies.     

New oral antidiabetic agents

The pathophysiology of hyperglycemia in type 2 diabetes (T2DM) involves 3 main defects: insulin deficiency, excess hepatic glucose output, and insulin resistance. Oral anti-diabetic agents act in a variety of ways. These include agents that stimulate insulin secretion, reduce hepatic glucose production, delay digestion and absorption of intestinal carbohydrate or improve insulin action. Because of improved knowledge of pathophysiology, new drugs with mechanisms of action focussed on specific pathophysiological alterations have appeared, in order to utilize all the possibilities of treating this condition. Here, we focus on the new agents used in the latest years and the overcoming ones in future, in particular incretin-based therapies, drugs inhibiting kidney glucose reabsorption (SGLT2 inhibitors), and glucokinase activators. The strategy for new drug development advocated here is to establish a broad range of anti-diabetic medicines with different mechanisms of action and potential opportunities for effective combination therapies.     

用Network Meta分析系统评价GLP-1受体激动剂类降糖药的心血管安全性

目的 使用Network Meta分析系统评价胰高血糖素样肽1（GLP-1）受体激动剂类降糖药的心血管安全性.方法 系统检索Medline、Embase、ClinicalTrials.gov和Cochrane Library数据库（截止2011年10月）中比较GLP-1受体激动剂与其他降糖药物或安慰剂的心血管安全性的随机对照研究（RCT）,采用传统Meta分析和Network Meta分析方法对纳入的RCT的研究结果进行合并.结果 共纳入45项研究,15 883例糖尿病患者,包括八种干预措施（六种GLP-1类药：艾塞那肽、利拉鲁肽、他司鲁肽、阿必鲁肽、利西拉来和LY2189265,以及安慰剂和传统降糖药）,研究总臂数为95.传统Meta分析和Network Meta分析结果相近,均未显示GLP-1受体激动剂与其他降糖药物或安慰剂之间心血管疾病安全性有统计学差异（P均＞0.05）.此外,结合直接和间接比较的Network Meta分析显示六种GLP-1类药之间两两比较的心血管安全性也均无统计学差异（P均＞0.05）.基于贝叶斯理论的Network Meta分析可对八种干预措施进行排序,显示安慰剂心血管风险最大.结论 尽管单个研究报道GLP-1类药有潜在的心血管保护效应,但目前Network Meta分析仍无法定论,仍有待专门设计的大型前瞻性研究加以验证.     

血糖波动的口服药物治疗

糖化血红蛋白(HbA1c)作为反映血糖状态的稳定指标,对判断血糖控制是否达标有重要意义.然而,越来越多的循证医学证据表明,血糖波动也是影响糖尿病患者并发症发生和预后的不可忽视的指标.多次指血糖测定以及动态血糖监测是发现血糖波动的主要方法.除胰岛素外,多种口服降糖药具有明确的降低餐后血糖的作用.从而减少血糖的波动.α-糖苷酶抑制剂、格列奈类以及短效磺脲类药物是控制餐后高血糖的主要药物,且具有各自的作用特点.     

New oral antidiabetic agents and current strategies of peroral antidiabetic therapy (PAD)

Optimal compensation in patients with type 2 diabetes is individualization of therapy according to the stage of the disease and ratio of the main pathophysiological disorders. Because of the hitherto inadequate effectiveness of known procedures attention is focused on seeking new more effective procedures either based on the use of known molecules of oral antidiabetics or introduction of new substances.     

Oral renin inhibitors

Use of drugs that inhibit the renin-angiotensin system is an effective way to intervene in the pathogenesis of cardiovascular and renal disorders. The idea of blocking the renin system at its origin by inhibition of renin has existed for more than 30 years. Renin inhibition suppresses the generation of the active peptide angiotensin II. The first generation of orally active renin inhibitors were never used clinically because of low bioavailability and weak blood-pressure-lowering activity. At present, aliskiren is the first non-peptide orally active renin inhibitor to progress to phase-III clinical trials. It might become the first renin inhibitor with indications for the treatment of hypertension and cardiovascular and renal disorders. Novel compounds with improved oral bioavailability, specificity, and efficacy are now in preclinical development. This Review summarises the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren.     

Metabolic syndrome therapy: Prevention of vascular injury by antidiabetic agents

More than 65 million Americans are currently obese. Type 2 diabetes mellitus, frequently seen in obese subjects, affects 17 million adults in the United States, with a continuous and alarmingly increasing rate. To prevent development of diabetes in those who are at high risk, it is recommended to optimize meal planning and enhance physical activity to make sustained weight reduction possible. In addition to lifestyle changes, various oral antidiabetic agents are available, with diverse mechanisms of action. Some target defective insulin secretion (sulphonylureas, benzoic acid derivatives) or glucose absorption (glycosidase inhibitors), whereas others target insulin resistance (metformin, thiazolidinediones). Patients with metabolic syndrome and diabetes have an increased risk for cardiovascular disease linked to a higher prevalence of hypertension, dyslipidemia, microalbuminuria, and altered hemostasis—parameters that may be modified by antidiabetic agents. In this article, we review the oral agents used to treat type 2 diabetes and the metabolic syndrome, and their effects on vascular tissue.     

Interactions of non-steroidal antirheumatic drugs with oral antidiabetic agents: acemetacin--glibenclamide

In a double-blind cross-over trial on 20 diabetic patients of type IIb we investigated whether a drug interaction between glibenclamide and acemetacin may possibly occur. After hospitalization of all in-patients needing glibenclamide therapy, a one-week period of adaptation to clinical conditions with optimized diet, antidiabetic dosage of the drug and the beginning of a diabetes learning programme followed. Thereafter, in a randomized design, ten out of the 20 patients were treated concomitantly with either 60 mg acemetacin t.i.d. or placebo for 1 week. Furthermore, a cross-over period of one week's duration followed once more. Daily blood glucose profiles (four values) were measured every second day and suggested a continuous improvement of the severe diabetic state previously seen. Blood glucose levels reached an optimal steady-state condition after 1 week of adaptation. Concomitant treatment with acemetacin did not lead to a relevant alteration of the laboratory parameters used in type IIb diabetic patients. This could also be established due to HbA1 values. Contrary to other nonsteroidal anti-inflammatory drugs, interactions between acemetacin and the widely used oral antidiabetic glibenclamide could not be established.     

Current and future aspects of oral antidiabetic agents in type 2 diabetes

Type 2 diabetes mellitus is characterized by insulin deficiency but in particular by insulin resistance. Patients where it is not possible to achieve positive results within 4-12 weeks by optimalization of the lifestyle are candidates for treatment with oral antidiabetics. At present the following main groups of oral antidiabetics are discussed: insulin secretagogues (SU derivatives and methiglinide derivatives), biguanides (Metformin), alpha-glucosidase inhibitors (acarbose, miglitol) and insulin sensitizers (thiazolindiones). Traditional SU therapy improves the insulin plasma levels by releasing insulin from the pancreas. This implies further stress on the b-cells and the function of these cells declines reversibly. Biguanides, such as metformin, are effective substances reducing the blood sugar level, they are however associated with the problem of tolerability and are contraindicated in some diabetics. A new approach to the treatment of type 2 diabetes are thiasolinediones, insulin-sensitizing substances, the molecular basis of their action being via activation of PPAR gamma-nuclear receptors with subsequent change in expression of genes participating in carbohydrate and lipid metabolism.     

Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug

Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A(1c) (HbA(1c)) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA(1c) reduction with DPP-IV inhibitors depends upon the pretreatment HbA(1c) values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes.     

Thrombin inhibitors as anticoagulant agents.

Hirudin and its analogues and the synthetic antithrombin agents are interesting new antithrombotic agents that have been studied in a number of well-designed randomized clinical trials and further studies are underway. These agents offer certain advantages over heparin and low-molecular-weight heparin, and at least one agent is orally bioavailable. Studies have shown that the specific thrombin inhibitors can significantly decrease the incidence of composite cardiac endpoints in acute ischemic syndromes (following thrombolysis for myocardial infarction, unstable angina, and non-Q wave myocardial infarction and coronary angioplasty), but it is disappointing that the benefits obtained during short-term treatment are not sustained in the long term. Recent data are reviewed here from clinical trials supporting the use of the specific antithrombin agents in the treatment of acute cardiac ischemic syndromes, the prevention and treatment of venous thromboembolism, and the management of heparin-induced thrombocytopenia.     

Angiotensin-converting enzyme inhibitors as cardioprotective agents

This discussion of documented and possible cardioprotective effects of angtotensin-converting enzyme (ACE) inhibitors examines the variety of sites along the pathway to end-stage heart disease at which they might intervene. In addition to their antihypertensive activity, their effects on left ventricular hypertrophy, lipid profiles, and insulin sensitivity are discussed in comparison to the effects of other classes of antihypertensive agents on these risk factors. The ability of ACE inhibitors to prevent the progression of congestive heart failure and reduce mortality is documented and a summary of data demonstrating benefits of their use in postmyocardial infarction patients with low ejection fraction is presented.     

不同种类口服降糖药联用对2型糖尿病患者动脉内膜中层厚度和斑块发生的影响

目的探讨不同种类口服降糖药联用对2型糖尿病患者动脉内膜中层厚度(intima-media thick-ness,IMT)和斑块发生率的影响。方法选取初发2型糖尿病患者139例(2002年),将患者分为一种、两种、三种口服降糖药物单用组(SING、DOUB、TRIP)和不使用口服降糖药物组(NONE)及对照组。对比分析随访第6年(07年)和第8年(09年)各组颈动脉、髂动脉及股动脉的IMT值与斑块发生率以及其他临床指标的变化情况。结果 (1)TRIP组09年胰岛素(insulin,INS)水平与07相比略有降低。(2)TRIP组09年动脉IMT与07年相比有下降趋势,而对照组动脉IMT值显著升高(P<0.05)。(3)TRIP组的动脉斑块发生率低于同期其他各组对应的动脉斑块发生率(P<0.05)。(4)口服降糖药物联用种类与动脉斑块发生率具有明显相关性(P<0.05)。(5)本研究证明INS是颈动脉斑块发生的危险因子(P<0.05),餐后2 h血糖(2hPG)和INS为髂动脉斑块发生的危险因子(P<0.05)。结论罗格列酮+二甲双胍+格列吡嗪三种口服降糖药联用的三联疗法能控制胰岛素升高,延缓甚至逆转脉内膜增厚进程并且能够抑制动脉斑块发生,是较全面的防治2型糖尿病大血管病变的综合疗法。