ACE inhibitors in patients with diabetes mellitus. Clinical and economic considerations

The advent of the ACE inhibitors has been one of the major developments in cardiovascular pharmacology this century. Aside from their role as potent anti-hypertensive drugs with few adverse effects, ACE inhibitors have numerous other effects that have only been partially explained. Antihypertensive therapy is the most effective treatment in patients with diabetic nephropathy, postponing the development of end-stage renal failure. Although this effect can apparently be obtained with all antihypertensives (except nifedipine), recent meta-analyses have indicated that the beneficial effects of ACE inhibitors on proteinuria and preserved renal function are greater than with other drugs. In nondiabetic patients, treatment with ACE inhibitors may delay or prevent the development of congestive heart failure following acute myocardial infarction. Whether this also occurs in diabetic patients is still unknown, but subgroup analysis of existing studies and controlled clinical trials in this area should be encouraged. In conclusion, ACE inhibitors are the only drugs that have been proven, in controlled clinical trials, to be effective in preventing progression from micro-albuminuria to overt nephropathy. Furthermore, they are more effective in diminishing albuminuria at low levels of blood pressure reduction compared with other antihypertensives. In comparison with beta-blockers, ACE inhibitors have the advantage that they do not mask the subjective symptoms of hypoglycaemia, nor do they affect the serum lipid profile.     

Cost effectiveness of ACE inhibitor treatment for patients with type 1 diabetes mellitus

OBJECTIVE: Current guidelines recommend treating patients with type 1 diabetes mellitus with ACE inhibitors after the onset of microalbuminuria. Recent clinical trials have shown ACE inhibitors can affect the development of nephropathy when initiated prior to the onset of microalbuminuria. Our objective is to examine the cost effectiveness of treating adults aged over 20 years with an ACE inhibitor (captopril) immediately following diagnosis of type 1 diabetes versus treating them after the onset of microalbuminuria. DESIGN: Using a semi-Markov model, we calculated four main outcome measures: lifetime direct medical costs (discounted), QALYs, cumulative incidence of end-stage renal disease (ESRD), and number of days of ESRD over a lifetime. Medical costs are in 1999 US dollars. SETTING: All analyses were from the viewpoint of a single US payer responsible for all direct medical costs, including screening for microalbuminuria, ACE inhibitor treatment (captopril), management of major diabetic complications, and routine annual medical costs not specific to diabetes. METHODS: We applied the model to a hypothetical cohort of 10,000 persons newly diagnosed with type 1 diabetes. Distribution of sex and race/ethnicity within the cohort is representative of the general US population. RESULTS: We estimated that the incremental cost of early use of captopril for the average adult with type 1 diabetes is USD 27,143 per QALY. This level varies considerably with age and glycaemic level. When the age at onset of diabetes is 20 years and glycosylated haemoglobin (HbA(1c)) level is 9%, the cost-effectiveness ratio is USD 13,814 per QALY. When the age at onset is 25 years and HbA(1c) level is 7%, the cost-effectiveness ratio is USD 39,530 per QALY. CONCLUSION: This model, with its underlying assumptions and data, suggests that early treatment with captopril provides modest benefit at reasonable cost effectiveness, from the US single-payer perspective, in the prevention of ESRD compared with delaying treatment until diagnosis of microalbuminuria. Early treatment with other ACE inhibitors will provide similar cost effectiveness if they have equivalent efficacy, compliance and price per dose. Treatment may be considered among patients at age 20 years with new onset of type 1 diabetes. This conclusion is sensitive to the extent that ACE inhibitors delay onset of microalbuminuria. Other factors such as the patient's age and glycaemic level must be considered when deciding to initiate early treatment.     

二甲双胍在老年2型糖尿病患者治疗中的作用

二甲双胍(Metformin)自1957年上市以来,已经在治疗糖尿病的征途上风风雨雨走过了50多年.实际上,早在一个世纪前科学研究者就在对山羊豆素样化合物的合成和药理学研究中发现了二甲双胍,但由于胰岛素和磺脲类药物的发现和使用,使二甲双胍的临床应用经历了曲折的道路.并且经受住了历史的考验,其在临床上的应用价值不断被发掘.2007年在美国糖尿病学会(ADA)糖尿病临床指南中,首次在控制高血糖的策略中推荐具体降糖药物使用的前后顺序和路径:生活方式干预的同时应用二甲双胍作为起始治疗,胰岛素强化合并二甲双胍及格列酮作为最终治疗.二甲双胍作为2型糖尿病的一线用药的地位得到了进一步确立和巩固.2008年ADA指南又提出其在预防和延缓2型糖尿病上的作用.     

Economic evaluation of ACE inhibitor treatment of nephropathy in patients with insulin-dependent diabetes mellitus in Italy

Diabetic nephropathy is one of the major complications of insulin-dependent diabetes mellitus (IDDM), with proteinuria being the main clinical manifestation of diabetic nephropathy. Most patients who develop overt proteinuria progress to end-stage renal disease (ESRD), usually within 5 to 7 years; ESRD necessitates dialysis or renal transplantation. Although a relationship between blood pressure reduction and delaying of ESRD has been assumed for a long time, only recently has a controlled randomised clinical trial shown that the treatment of diabetic nephropathy with an ACE inhibitor can significantly delay the loss of renal function and, therefore, ESRD. Consistent with the clinical trial on which this economic evaluation was based, the costs and consequences of 2 alternatives were considered: (i) patients subject to blood pressure control with only antihypertensive medication, but without an ACE inhibitor (placebo group) and (ii) patients given ACE inhibitor therapy (captopril group) with similar blood pressure control to the placebo group. This cost-effectiveness analysis was performed from the perspective of the Italian National Health Service [Servizio Sanitario Nazionale (SSN)]. Accordingly, only direct costs related to publicly funded healthcare services were included. The number of dialysis-years avoided (DYA) was the clinical end-point. A 10-year time horizon was considered for the economic evaluation. Captopril therapy was dominant, being at the same time more effective and less costly. The total cost for the captopril alternative during the 10-year period was 21,901,625 Italian lire (L; 1993 values) per patient, while total cost for the placebo alternative was L30,352,590 per patient. Compared with placebo, 20.01 DYA per 100 patients treated were estimated with captopril therapy during the trial period, equivalent to 2.4 months per patient. The robustness of this result was confirmed by sensitivity analysis: for both extremes, captopril remained dominant. This economic evaluation, requested by the Italian Ministry of Health, demonstrated savings in healthcare expenditure with the use of an ACE inhibitor in patients with proteinuria.     

ACE inhibitors in pediatric patients with heart failure

This article reviews reports of ACE inhibitor use in pediatric heart failure and summarizes the present implications for clinical practice. Captopril, enalapril, and cilazapril are orally active ACE inhibitors, and widely used in pediatric cardiology, although more than ten other ACE inhibitors have been applied clinically in adults. Effects of ACE inhibitors on the renin-angiotensin-aldosterone system in pediatric patients are similar to those in adults. ACE inhibitors lower aortic pressure and systemic vascular resistance, do not affect pulmonary vascular resistance significantly, and lower left atrial and right atrial pressures in pediatric patients with heart failure. In infants with a large ventricular septal defect and pulmonary hypertension, ACE inhibitors decrease left-to-right shunt in those infants with elevated systemic vascular resistance. ACE inhibitors induce a small increase in left ventricular ejection fraction, left ventricular fractional shortening, and systemic blood flow in children with left ventricular dysfunction, mitral regurgitation, and aortic regurgitation. These beneficial effects usually persist long term without the development of tolerance. Therapeutic trials of ACE inhibitors have been reported in children with heart failure and divergent hemodynamics, including myocardial dysfunction, left-to-right shunt, such as large ventricular septal defect and pulmonary hypertension, aortic or mitral regurgitation, and Fontan circulation.Hypotension and renal failure usually occur within 5 days after starting ACE inhibition or increasing the dose and, in most cases, recovery is seen after reduction or cessation of the drug. With all ACE inhibitors, smaller doses are administered initially to prevent excessive hypotension, and doses are increased gradually to the target dose. Captopril is administered orally, usually every 8 hours. Daily doses range from 0.3 to 1.5 mg/kg in children. Enalapril is administered orally, once or twice a day, and daily doses range from 0.1 to 0.5 mg/kg. Enalaprilat is administered intravenously, one to three times a day, in doses ranging from 0.01 to 0.05 mg/kg/dose.For the treatment of chronic heart failure in children, ACE inhibitors are essential along with other medications including diuretics, digoxin, and beta-blockers (beta-adrenoceptor antagonists).     

Pulmonary function in patients with diabetes mellitus.

The present study was carried out to assess the lung functions in oral medicated and insulin administered patients with normal controls. 20 subjects were selected as the study group for oral medication (Group I), 20 subjects were selected as the study group for insulin treatment (Group II) and 40 subjects were selected as normal controls. Age group of Group I and Group II were 51.25 +/- 6.28 and 50.8 +/- 6.56 respectively and controls were age and height matched. Seventeen patients of Group I were undergoing treatment for the last 10-20 years and 20 patients in Group II were undergoing treatment for the last 30 years. Only male subjects were selected for the study. Lung function test were carried out with Spirometer (Vitallograph Compact II). A significant reduction in forced expiratory volume/forced vital capacity (FEV1/FVC%) was observed in oral pills used subjects and insulin administered subjects as compared to controls. Significant decrease in forced expiratory flow rate (FEF25-75%) in group I subjects was also observed as compared to controls. Forced mid flow time (FMFT) showed a significant increase in group II in comparison to controls. These changes clearly show the expiratory flow rates are reduced both in orally medicated and insulin administered patients. Increase in FMFT in group I may be due to the reduced respiratory ability to carry out the FVC test along with the side effects of oral medication for diabetes mellitus.     

Interaction between aspirin and ACE inhibitors in patients with heart failure.

Both aspirin (acetylsalicylic acid) and ACE inhibitors are often used concomitantly, especially in patients with both heart failure and ischaemic heart disease, which is the most common underlying cause of heart failure. The safety of the association has been questioned because both drugs affect a related prostaglandin-mediated pathway. Thanks to their vasodilating properties, prostaglandins play an important role in heart failure where peripheral vasoconstriction occurs. Some of the beneficial effects of ACE inhibitors might be related to reduced degradation of bradykinin that enhances the synthesis of prostaglandins, while aspirin, through inhibiting the enzyme cyclo-oxygenase, inhibits the production of prostaglandins. To date no prospective study has been conducted to investigate the effect of long term aspirin treatment in the postinfarction period allowing the possible impact of the interaction between aspirin and ACE inhibitors upon survival to be confirmed or negated. However, the practitioner needs to know how to optimise the treatment of his or her patients. In order to stimulate arguments for and against the use of aspirin in patients with heart failure receiving ACE inhibitors, we searched MEDLINE from 1960 to 2000 using the key words heart failure, aspirin, and ACE inhibitors for English language articles and conducted a review of the available data. We report on the potential mechanisms of the interaction and the results of experimental studies on haemodynamic parameters. Results of retrospective clinical studies, subgroup analysis that were undertaken to evaluate the overall action upon haemodynamic parameters and survival of the association are summarised. Conflicting conclusions have been reported in the literature. Many explanations can be advanced to try to understand these conflicting conclusions: differences in study design (results of retrospective trials have to be interpreted with caution); differences in the choice of the evaluation parameter (problem of the clinical relevance of haemodynamic parameters); differences in the characteristics of the patient (different underlying cardiopathy, e.g. heart failure, hypertension or ischaemic cardiopathy); and differences in the type and the dosage of each treatment (especially ACE inhibitors and aspirin since an interaction might occur more often with dosage of aspirin greater than 250mg).     

糖尿病相关皮肤病变

由于血糖长期慢性升高而导致的各种急慢性并发症是糖尿病患者寿命缩短、生活质量下降的重要原因。糖尿病引起的皮肤病变虽不像心、脑、肾、眼病那样直接危害生命，但也给患者带来很多痛苦，如处理不好也会导致严重后果。     

Acute pancreatitis in patients with type 2 diabetes mellitus treated with dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase (DPP)-4 inhibitors are approved for use in monotherapy or in combination therapy for patients with type 2 diabetes mellitus for <1 decade. However, numerous reports of DPP-4 inhibitors induced acute pancreatitis were made through the US Food and Drug Administration Adverse Event Reporting System, and this led to a revision in the prescribing information for these drugs. Therefore, this study is designed to evaluate DPP-4 inhibitors induced acute pancreatitis via the spontaneous adverse drug reactions (ADRs) reporting system in a medical center. In four of 2305 ADR cases, it is suspected that DPP-4 inhibitors induced moderate to serious acute pancreatitis. Beyond drugs, other factors also contribute to acute pancreatitis and affect the possibility of ADRs assessed using the Naranjo algorithm. Finally, our results indicate that the incidence of DPP-4 inhibitors induced acute pancreatitis is low.     

ACE inhibitors and angiotensin receptor antagonists and the incidence of new-onset diabetes mellitus: an emerging theme

The prevalence of type 2 diabetes mellitus continues to rise. Given the associated co-morbidities of obesity, hypertension and cardiovascular disease, the rising incidence of diabetes has important health consequences and efforts to reduce this incidence are critical. Although lifestyle modifications, including weight loss and exercise, are instrumental in the prevention of diabetes, pharmacological therapies that reduce the incidence of diabetes have the significant potential to lower risk.The results of several large clinical trials have demonstrated that treatment with ACE inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) may prevent or delay the onset of diabetes. These trials have demonstrated an approximately 15-30% reduction in the new onset of diabetes in those receiving ACE inhibitors and ARBs when compared with placebo or other active therapy. Although the exact mechanism underlying the effects are not entirely clear, multiple animal and human studies have demonstrated that the renin-angiotensin system plays an important role in glucose homeostasis. Although future prospective studies to clarify the role of ACE inhibitors and ARBs in preventing diabetes are ongoing, there is substantial existing evidence from completed trials that these agents may prevent the onset of diabetes.     

Paracetamol elimination in patients with non-insulin dependent diabetes mellitus.

The pharmacokinetics and metabolism of an intravenous dose (500 mg) of paracetamol were studied in a group of non-insulin dependent diabetic patients (n = 10) and in a group of healthy control subjects (n = 9). Paracetamol clearance, half-life and the partial clearance to paracetamol glucuronide were not significantly different, but the partial clearance to paracetamol sulphate was significantly reduced (62 +/- 18 vs 86 +/- 17 ml h-1 kg-1 (mean +/- s.d.)) and the renal clearance of paracetamol was significantly increased (56 +/- 20 vs 22 +/- 6 ml h-1 kg-1 (mean +/- s.d.)) in the non-insulin dependent diabetic patients, compared with the control group.     

Managing hypertension in patients with type 2 diabetes mellitus.

PURPOSE: Current guideline recommendations for effective strategies to optimize the treatment of patients with concomitant hypertension and type 2 diabetes mellitus are reviewed. SUMMARY: Current estimates indicate that 20 million people in the United States have diabetes, 90-95% of whom have type 2 diabetes mellitus. Type 2 diabetes mellitus is associated with an increased risk of premature death from cardiovascular disease (CVD), stroke, and end-stage renal disease. Hypertension is an extremely common comorbidity in patients with type 2 diabetes mellitus. The coexistence of hypertension in patients with type 2 diabetes is particularly destructive because of the strong linkage of the two conditions with CVD, stroke, progression of renal disease, and diabetic nephropathy. Current guidelines, including those issued by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the National Kidney Foundation, and the American Diabetes Association, provide evidence-based recommendations for the treatment of hypertension in patients with type 2 diabetes mellitus. However, studies indicate that guidelines are not widely followed. Therefore, the beneficial effects of appropriate hypertension treatment observed in clinical trials are often not recognized in clinical practice. Pharmacists are ideally positioned to help improve guideline implementation and patient outcome. CONCLUSION: Pharmacists must become more vigilant about following current guidelines for the treatment of patients with concomitant hypertension and type 2 diabetes mellitus. Strategies such as patient education and medication assessment can help to optimize care for these patients and slow the progression to diabetic nephropathy.     

Antiplatelet therapy in patients with diabetes mellitus

Platelets are key players in arterial thrombosis, and oral antiplatelet therapy is a cornerstone in the treatment and prevention of cardiovascular events. However, although currently approved antiplatelet drugs have proved successful in reducing cardiovascular events, platelet-dependent thrombosis remains an important cause of morbidity and mortality in patients with coronary artery disease. It is well-known that patients with diabetes mellitus (DM) have an increased risk of cardiovascular events and, therefore, understanding the mechanism of action and safety profile of antiplatelet drugs in this high-risk population is of particular interest. There is considerable inter-individual variation in the efficacy of established antiplatelet drugs, and high on-treatment platelet reactivity is associated with an increased risk of cardiovascular events, thus prompting the search for novel drugs against platelet-dependent thrombosis. New antiplatelet treatment strategies include drugs with more efficient and reversible platelet inhibition. This review discusses selective inhibitors of the platelet cyclooxygenase enzyme, thienopyridine and non-thienopyridine inhibitors of the platelet adenosine diphosphate receptor, phosphodiesterase inhibitors, and protease-activated receptor antagonists. An overview of currently available antiplatelet drugs is provided, focusing on benefits and limitations in patients with DM. Furthermore, the rationale for new oral antiplatelet drugs under development is discussed with particular focus on the potential role of these drugs to improve cardiovascular outcomes in patients with DM.     

糖尿病患者心率变异性分析

采用程度静态分域分析法及频域分析检测了４６例糖尿病（ＤＭ）患者的心率变异性（ＨＲＶ）。时域分析表明ＤＭ患者减小，频域分析提示ＤＭ患者心脏自主神经系统失衡，交感神经张力相对增高，副交感神经活性相地降低，相关分析显示ＤＭ患者之经血红蛋白浓度和周围神经平均传导速度与其ＨＲＶ变化之间存在关联。     

Serum fructosamine in patients with diabetes mellitus

Serum fructosamine was compared with other measures of blood glucose control in 11 non-diabetic volunteers, 14 type 1 and 14 type 2 diabetic patients. Estimates of mean plasma glucose concentrations for the 28 diabetic patients were made by nine physicians, based on their interpretation of historical data, home capillary blood glucose profiles, fasting and random plasma glucose and plasma lipid levels. Significant differences between estimated and measured mean glucose levels were apparent with a tendency for physicians to underestimate mean blood glucose in the hyperglycaemic range (glucose greater than 11 mmol/l). Fructosamine results on the same patients correlated linearly both with mean plasma glucose concentrations (r = 0.86, p less than 0.001) and with glycosylated haemoglobin (HbA1c) levels (r = 0.93, p less than 0.001) and correctly classified diabetes control in most patients. Despite marked fluctuations of plasma glucose concentration, serum fructosamine levels measured at different times of the day did not alter significantly. We conclude that a random serum sample analysed for fructosamine provides a simple and reliable means to measure the efficacy of therapy and often provides information superior to clinical assessment of diabetic control.     

Altered redox status in patients with diabetes mellitus type I.

Diabetes mellitus is a complex metabolic disorder characterized by a disturbance in glucose metabolism. Recent evidences suggest that increased oxidative damage as well as deficits in antioxidants defence systems could be related to the complications in Diabetes patients' type I. The aim of this study was to investigate an extensive array of redox status indices: glutathione (GSH), malondialdehyde (MDA), peroxidation potential, superoxide dismutase (SOD), catalase (CAT), total hydroperoxide (TH) and advanced oxidation protein products (AOPP) in relation to blood glucose and glucose indicators control such as glycosylated haemoglobin (HbA1c) and fructosamine by spectophotometric techniques. Forty Diabetes Mellitus patients' type I and 40 healthy subjects were recruited. Both a reduction of GSH levels and an increase in MDA and TH levels were observed in the serum of patients. These patients also showed an increase of AOPP and PP levels as well as an increase of both CAT and SOD activity. Relatively to the control group, patients had significant differences in global indices of oxidant/antioxidant status and indicators of glycaemia control. These results contribute both to the evidences that substantial oxidative stress occurs during Diabetes Mellitus type I without early complications and to an integral overview of the oxidant/antioxidant balance in these patients.     

钠-葡萄糖转运蛋白2抑制剂与2型糖尿病患者恶性肿瘤发生风险的Meta分析

目的： 系统评价钠-葡萄糖转运蛋白2（sodium-glucose transporter 2 inhibitors,SGLT2）抑制剂的使用与2型糖尿病患者肿瘤发病的关系,为明确二者之间关系提供循证医学依据。方法： 以"钠-葡萄糖转运蛋白2（SGLT2）抑制剂、达格列净（dapagliflozin）、坎格列净（canagliflozin）、恩格列净（empagliflozin）、2型糖尿病、肿瘤"等为关键词,通过PubMed、Embase、Web of Science、Cochrane Library及万方、中国知网（CNKI）、维普中文期刊（VIP）等数据库检索2021年2月以前发表的中英文文献,确定符合条件的随机对照试验（randomized controlled trials,RCTs）。运用RevMan 5.3和Stata 15.0软件进行统计学处理。结果： 最终纳入17篇文献,共35 299例患者,其中1 072例2型糖尿病患者罹患恶性肿瘤。Meta分析结果表明,与对照组相比,SGLT2抑制剂与总体肿瘤风险增加无显著相关性（RR=0.98,95% CI：0.96~1.36）。不同SGLT2抑制剂对肿瘤发生的风险无显著相关性（RR=0.92,95% CI：0.81~1.04）。结论： 目前来自短期随机对照试验的证据并未表明使用SGLT2抑制剂的2型糖尿病患者有增加发生恶性肿瘤的风险。