肾素-血管紧张素系统抑制药和糖尿病

血管紧张素转换酶抑制药(ACEI)和血管紧张素Ⅱ受体1拮抗药(ARB)是目前抑制肾素-血管紧张素系统的主要药物大量研究结果表明ACEI和ARB不仅可降低糖尿病的发生率、延迟糖尿病的进展,而且可降低糖尿病患者心血管事件的发生率和心血管死亡率。本文对其作用及机制进行探讨     

Dapagliflozin for the treatment of type 1 diabetes mellitus

Introduction: In 2017, the management of type 1 diabetes mellitus (T1DM) remains intriguing for the clinician, who has to balance between adequate glycemic control and untoward events related to insulin up-titration. Thus, agents that will complement insulin actions and reduce adverse effects are highly welcome.

Areas covered: In this review, the authors summarize results from studies on the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin in T1DM.

Expert opinion: In T1DM, dapagliflozin is associated with significant antihyperglycemic and metabolic properties, which are achieved with reduction or stabilization of insulin dose and with a very low trend for hypoglycemia. However, there is a lot to learn with respect to diabetic ketoacidosis (DKA), bone fractures and lower limb ischemia.     

Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus

Introduction: Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 – 7.0% range. Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in T2DM. We examine combination therapy with linagliptin plus empagliflozin as a therapeutic approach for the treatment of inadequately controlled T2DM patients.

Areas covered: A literature search of all human diabetes, metabolism and general medicine journals from year 2000 to the present was conducted. Glucagon like peptide-1 (GLP-1) deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. DPP-4 inhibitors (DPP4i) improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Linagliptin, a DPP-4 inhibitor, reduces HbA1c, is weight neutral, has an excellent safety profile and a low risk of hypoglycemia. The expression of sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule is upregulated in T2DM, causing excess reabsorption of filtered glucose. The SGLT2 inhibitor (SGLT2i), empagliflozin, improves HbA_1c by causing glucosuria and ameliorating glucotoxicity. It also decreases weight and blood pressure, and has a low risk of hypoglycemia.

Expert opinion: The once daily oral combination of linagliptin plus empagliflozin does not increase the risk of hypoglycemia and tolerability and discontinuation rates are similar to those with each as monotherapy. At HbA1c values below 8.5% linagliptin/empagliflozin treatment produces an additive effect, whereas above 8.5%, there is a less than additive reduction with combination therapy compared with the effect of each agent alone. Linagliptin/empagliflozin addition is a logical combination in patients with T2DM, especially those with an HbA1c < 8.5%.     

Preventing and treating kidney disease in patients with type 2 diabetes

Introduction: Chronic kidney disease (CKD) represents a huge burden in patients with type 2 diabetes (T2DM). This review therefore has the aim of assessing the add-on value of new glucose-lowering agents compared or combined with inhibitors of the renin angiotensin aldosterone system (RAAS) on renal outcomes in T2DM patients.

Areas covered: This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development.

Expert opinion: RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucose-lowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end-stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM.     

Sotagliflozin as a potential treatment for type 2 diabetes mellitus

Introduction: SGLT1 is the primary transporter responsible for the absorption of glucose and galactose in the intestine, while SGLT2 and SGLT1 are both involved in the renal reabsorption of glucose. SGLT2 inhibitors are a new class of oral antidiabetic drugs, acting by increasing urinary glucose excretion (UGE). They offer the advantages of a reduced risk of hypoglycaemia, a decrease in body weight and blood pressure and an efficacy at all stages of type 2 diabetes (T2DM).

Areas covered: Herein, the authors focus specifically on sotagliflozin (LX4211), the first-in-class dual SGLT1/SGLT2 inhibitor. Original publications in English were selected as the basis of this review. Clinical trials were identified using the Clinicaltrial.gov database.

Expert opinion: By a potential additional mechanism of action on intestinal glucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from SGLT2 inhibitors by reducing postprandial glucose excursion and insulin secretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on UGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 inhibitors on HbA1C reduction, with a similar safety profile in short-term studies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 development as an adjuvant treatment in patients with T1DM after positive results from a pilot study.     

Ongoing clinical trials in systemic hypertension

Hypertension was identified as a cardiovascular risk factor in the late fifties and still remains a public health issue. The number of patients treated reaches only half of those diagnosed and, of those treated, half fail to reach target blood pressure. Furthermore, the number of antihypertensive drugs reaching the market has increased exponentially in the last few years, however, the impact on treatment and on attaining target blood pressure levels remains to be seen. The high percentage of treated patients who do not reach target blood pressure, combined with the high number of patients requiring more than one antihypertensive drug, have triggered a series of long-term morbidity and mortality trials comparing different therapeutic approaches (‘new’ pharmacological classes vs. ‘old’ pharmacological classes). These are described in this paper.     

Empagliflozin added to metformin and sulfonylurea therapy in patients with sub-optimally controlled type 2 diabetes mellitus

The combination of metformin and a sulfonylurea is commonly used in type 2 diabetes mellitus. Many patients on this combination therapy do not achieve or maintain glycemic targets and require the addition of a third antihyperglycemic agent. Among the options are the sodium glucose cotransporter 2 (SGLT2) inhibitors, a recently developed class of medications that effectively improve glycemic control and are associated with reduction in body weight and blood pressure. This article evaluates a 24-week, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin, added to metformin plus sulfonylurea regimens. Empagliflozin led to significant reductions in glycated hemoglobin and fasting plasma glucose, as well as body weight and systolic blood pressure. Adverse events typically recorded with SGLT2 inhibitors were observed; notably, genital infections occurred in more patients on empagliflozin than placebo. Overall, empagliflozin was well tolerated. These results indicate that SGLT2 inhibitors can be successfully added to metformin plus sulfonylurea regimens. SGLT2 inhibitors are not the only therapeutic option in this clinical situation; however, based on the secondary effects observed in this and other studies, they appear to be of particular value for patients who are obese or overweight.     

肾素-血管紧张素系统抑制剂治疗高血压的研究进展

高血压是引起心血管疾病和导致死亡的最主要原因之一。肾素-血管紧张素系统在高血压的病理生理机制中起着关键作用。肾素-血管紧张素系统抑制剂在治疗高血压中的应用最为广泛。已有许多大型临床研究评价了血管紧张素转化酶抑制剂、血管紧张素Ⅱ受体拮抗剂和肾素抑制剂单用或联用治疗高血压的作用。本文就近年来肾素-血管紧张素系统抑制剂治疗高血压的研究进展作一综述。     

The latest pharmacotherapy options for type 1 diabetes

Introduction: Pharmacotherapy of type 1 diabetes (T1D) is mainly restricted to insulin treatment. Insulin analogues have replaced human insulin sometimes without reason. A broader approach is needed.

Areas covered: Insulin and insulin analogues, but also other available hormone therapies and drugs, based on literature in PubMed are included in this study.

Expert opinion: At diagnosis, T1D patients should, when resources allow, participate in clinical trials aiming at preservation of beta cell function, for example, with combination therapies involving auto-antigen/s. In very young children insulin pump is recommended, when enough resources for ALL patients; in older patients pump or multiple insulin therapy is recommended. Human insulin still has a place, with insulin analogues on special indications. Patients with pronounced insulin resistance might need Metformin, and Glitazones need more studies. Incretins, for example, GLP-1 may be of interest in patients with residual C-peptide. Amylin will probably be restricted to highly motivated patients. IGF-1 also requires more studies. C-peptide may be a hormone, probably part of future treatment. Glucosoxidase inhibitors might be considered in obese patients. Whether drugs increasing glucosuria will be of clinical value in T1D remains to be shown. In summary, insulin replacement is not enough for several patients. A broader pharmacotherapy is needed, at onset, and later when metabolic control needs improvement.     

Therapeutic potential of ACE inhibitors for the treatment of hypertension in Type 2 diabetes

Type 2 diabetes mellitus is associated with hypertension. If untreated, hypertension has a major impact on the clinical course of Type 2 diabetes and its vascular complications. In this review, we discuss rationale for the use of ACE inhibitors (ACEI) in hypertensive Type 2 diabetic patients and compare those theoretical assumptions with results of recent major clinical trials. Furthermore, possible directions for future clinical and experimental research are outlined. The RAS and its effector angiotensin II are important players in a number of cardiovascular and renal disorders. Recent evidence suggests that RAS and factors functionally linked to RAS are activated in Type 2 diabetes. Therefore, there is a theoretical basis for the use of ACEI in the treatment of hypertension in diabetic patients. Some recent studies reported superior outcome in patients treated with ACEI-based antihypertensive regimens compared with non-ACEI based treatments in reducing the risk of macrovascular disease (CAPPP, FACET, ABCD) or both micro- and macrovascular complications in Type 2 diabetes (HOPE). However, at least two of the large prospective studies discussed in this review (UKPDS 38, HOT), supported by results from previously published SHEP study, have recently suggested that the degree of reduction of blood pressure, rather than the choice of a particular class of antihypertensive agent, is associated with decreased risk of cardiovascular events. Studies focusing on renal end-points suggest that ACEI have a superior antiproteinuric effect than the other agents. However, whether ACEI are more nephroprotective, as assessed by the rate of decline in renal function, still remains to be elucidated. Despite promising results from recent trials, large numbers of patients progress despite ACEI treatment. Incomplete inhibition of the RAS may underlie this phenomenon. Treatment strategies that could enhance the degree of RAS inhibition represent one possible direction for clinical research in the near future. However, it is unlikely that the course of such a complex syndrome as Type 2 diabetes could be dramatically changed by just one class of antihypertensive agents. This goal is more likely to be achieved by multifactorial intervention, reflecting the complexity of metabolic syndrome. ACEI should be viewed as an important, but not the only, part of this complex approach.     

肾素-血管紧张素系统阻断剂与代谢综合征患者脂联素水平的关系

目的探讨肾素-血管紧张素系统（RAS）阻断剂与代谢综合征（Mets）患者血浆脂联素水平的关系。方法53例Mets患者随机分为3组,ACEI组15例予贝那普利（5 mg/d）,ARB组15例予坎地沙坦（4 mg/d）,对照组23例避免应用影响RAS的相关药物,服药期为4周,检测并比较治疗前后血浆脂联素（APN）、空腹血糖（FBG）、空腹胰岛素（FINS）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）、总胆固醇(TC)、低密度脂蛋白胆固醇（LDL-C）、肌酐（CR）、丙氨酸转氨酶（ALT）、胆红素（BIL）和胰岛素抵抗指数（HOMA-IR）的水平。结果 ACEI组的FBG和LDL-C、ARB组的CR治疗后低于治疗前（P＜0.05）;ACEI组和ARB组APN水平治疗后高于治疗前（P＜0.01）,而3组中FINS、HOMA-IR、TC、ALT和BIL在治疗前后变化差异无统计学意义（P＞0.05）。治疗前CR、TC、ALT和BIL是APN水平的影响因素;治疗后FBG和TC是APN水平的影响因素。结论 APN可能是ACEI和ARB治疗Mets及其并发症的潜在靶点。     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT₁) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT₁ receptors (postsynaptically) and at presynaptic AT₁ receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

2型糖尿病新一代降糖药的药物基因组学的最新进展

精准医学是综合考虑个人的基因、环境和生活方式的一种新的疾病预防和治疗理念.随着药物遗传学和药物基因组学迅速发展和壮大,对个体遗传变异和药物剂量与治疗反应之间的联系进行研究,成为精准医学治疗的关键.2型糖尿病是一种以高血糖为特征的慢性代谢性疾病,可以导致心血管、肾脏等并发症.最新美国糖尿病协会和欧洲糖尿病协会的2型糖尿病...     

全国多中心564 711例高血压患者RAS抑制剂药物利用分析

目的：分析2017年全国8个城市口服RAS抑制剂的高血压患者特征和药品使用特征,为临床合理用药提供参考。方法：基于2017年《医院处方分析项目》随机抽取的处方数据,采用WHO推荐的药物利用分析方法,对ACEI和ARBs使用情况进行分析。结果：共抽得8个城市101家医院的564 711例的口服ACEI和ARBs类降血压药高血压患者。北京地区患者最多,占26.20%。男女比例为1.17。中位年龄64岁。老年患者占比49.90%。患者主要于门诊购药,占89.10%。处方科室以内科为主,占89.40%。303例患者存在潜在超适应证用药风险。ARBs处方数量占78.71%,处方金额占83.05%。处方数量和处方金额最大的3种药品依次为：缬沙坦、厄贝沙坦和氯沙坦;其PDD/DDD值均大于1：缬沙坦（1.32±0.53）、厄贝沙坦（1.33±0.87）和氯沙坦（1.70±0.65）;合并肾病、肝病及同时合并肾病和肝病患者的PDD/DDD值高于患者平均水平。结论：ARBs是临床更常用的RAS抑制剂,特别是缬沙坦、厄贝沙坦和氯沙坦;仍须规范ARBs和ACEIs类药物的适应证,且重视高血压合并肾病、肝病患者的药物剂量管理。     

Current treatment of hypertension in patients with coronary artery disease recommended by different guidelines

Introduction: It is important to know how to treat hypertension in patients with coronary artery disease (CAD). The reason for the review was to update this treatment and to discuss the 2015 American Heart Association/American College of Cardiology/American Society of Hypertension 2015 guidelines of treatment of hypertension in patients with CAD.

Areas covered: Studies between 1968 and 2015 were reviewed on treatment of hypertension in patients with CAD using a Medline search, and studies between 1977 and 2015 were reported. Hypertension should be treated with beta blockers and ACE inhibitors or angiotensin receptor blockers (ARBs). Long-acting nitrates are effective antianginal and anti-ischemic drugs. Calcium-channel blockers (CCBs) may be added if angina persists despite beta blockers and long-acting nitrates. The 2015 guidelines recommend that the blood pressure should be < 140/90 mm Hg in patients aged ≤ 80 years and the systolic blood pressure < 150 mm Hg if they are ≥ 80 years.

Expert opinion: Hypertension in patients with CAD should be treated with beta blockers and ACE inhibitors or ARBs. Long-acting nitrates are effective antianginal and anti-ischemic drugs. CCBs may be added if angina persists despite beta blockers and long-acting nitrates. The blood pressure should be < 140/90 mm Hg in patients aged < 80 years and the systolic blood pressure < 150 mm Hg if they are ≥ 80 years.     

Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus

Abstract

Objective: To assess the efficacy and safety of the sodium–glucose cotransporter 2 inhibitor ertugliflozin across racial groups in patients with type 2 diabetes mellitus (T2DM).

Methods: Pooled analysis of data from randomized, double-blind studies in the ertugliflozin phase III development program. Seven placebo- and comparator-controlled studies were used to assess safety (N?=?4859) and three placebo-controlled studies were used to assess efficacy (N?=?1544). Least-squares (LS) mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).

Results: At Week 26, ertugliflozin provided a greater reduction in HbA1c, body weight and SBP versus placebo in all racial subgroups. The placebo-adjusted LS mean change (95% confidence interval) from baseline in HbA1c was ?0.8% (?1.0, ?0.7) and ?1.0% (?1.1, ?0.8) with ertugliflozin 5?mg and 15?mg, respectively, in the White subgroup, ?0.7% (?1.2, ?0.2) and ?0.8% (?1.3, ?0.3) in the Black subgroup, and ?0.8% (?1.1, ?0.5) and ?1.0% (?1.3, ?0.8) in the Asian subgroup. The incidences of overall AEs, serious AEs and AEs leading to discontinuation from study medication were similar between the ertugliflozin 5?mg, 15?mg and non-ertugliflozin groups within each racial subgroup. The incidence of female genital mycotic infection (GMI) was higher with ertugliflozin than non-ertugliflozin across all racial subgroups. The incidence of male GMI was higher with ertugliflozin than non-ertugliflozin in the White sub-group; however, there were few male GMI events in the non-White subgroups.

Conclusions: In patients with T2DM, treatment with ertugliflozin improved HbA1c, body weight and SBP across all racial subgroups. Ertugliflozin had a generally similar safety profile across racial subgroups and was generally well tolerated.

Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.     

Empagliflozin/linagliptin single-pill combination therapy for patients with type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is typically progressive, with sequential addition of therapies often needed to address increasing hyperglycemia over the disease course. Using treatments in combination may be preferred to sequential addition, as a means of providing a more rapid clinical response and potentially avoiding clinical inertia. In such cases, a single-pill combination can help to reduce pill burden. Although various single-pill combinations of oral glucose-lowering agents are available, empagliflozin/linagliptin was the first approved combination of a sodium glucose co-transporter 2 (SGLT2) inhibitor with a dipeptidyl peptidase 4 (DPP-4) inhibitor in the United States.

Areas covered: Two publications of the clinical trial investigating the efficacy and safety of single-pill combinations of empagliflozin/linagliptin in treatment-naive or metformin-treated patients with T2DM (NCT01422876) are reviewed, and their potential impact on clinical practice is discussed.

Expert opinion: The study discussed provides evidence for the efficacy and safety of empagliflozin/linagliptin single pills. Addition of an empagliflozin/linagliptin single pill may be considered in patients with inadequate glycemic control on metformin, or as an alternative to first-line treatment with empagliflozin or linagliptin when metformin is not suitable, particularly in patients with very poor glycemic control, or those who need to achieve target more quickly.     

Novel blood glucose lowering therapies for managing type 1 diabetes in paediatric patients

Introduction: Therapy for type 1 diabetes (T1D) is mainly restricted to insulin treatment. The management of paediatric patients with T1D should tackle not only glucose control, but also insulin resistance, beta-cell preservation, quality of life and cardiovascular disease risk factors, which are increasingly recognized to occur in adolescents with T1D.

Areas covered: This review examines the recently published literature from PubMed on non-insulin agents for the management of T1D in paediatric patients.

Expert opinion: Few paediatric patients with T1D are achieving their metabolic targets. Current data support the need for new strategies and the consideration of additional therapies that not only may help patients, their families and their physicians to meet HbA1c targets, but also may preserve residual islet mass and good quality of life and prevent microvascular and macrovascular complications, thereby, reducing hypoglycaemic episodes. Non-insulin adjunctive therapies may improve not only glucose control, but also insulin sensitivity, in addition to preserving beta-cell function in T1D patients. Thus, more studies are required to define the potential role of these therapies in the management of paediatric patients.