Glucagon-like peptide-1 receptor agonists and pancreatitis: A meta-analysis of randomized clinical trials

Aims

Several randomized trials with metabolic outcomes have reported that glucagon like peptide-1 receptor agonists (GLP-1 RA) could be associated with an increased risk of pancreatitis. The present meta-analysis aimed to examine this hypothesis.

Methods

An extensive Medline, Embase, and Cochrane Database search for “exenatide”, “liraglutide”, “albiglutide”, “taspoglutide”, “dulaglutide”, “lixisenatide”, and “semaglutide” was performed up to March 31st, 2013. Inclusion criteria: (i) randomized trials, (ii) duration ≥12 weeks; (iii) on type 2 diabetes; and (iv) comparison of GLP-1RA with placebo or active drugs. Mantel–Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for pancreatitis.

Results

80 eligible trials were identified. Of these, 39 had not disclosed their findings or did not report any information on pancreatitis. The remaining 41 trials enrolled 14,972 patients, with a total exposure of 14,333 patient × years (8353 and 5980 patient × years for GLP-1 receptor agonists and comparators, respectively). The overall risk of pancreatitis was not different between GLP-1RA and comparators (MH-OR: 1.01[0.37; 2.76]; p = 0.99).

Conclusions

The present meta-analysis does not suggest any increase in the risk of pancreatitis with the use of GLP-1RA. However, it should be recognized that the number of observed cases of incident pancreatitis is very small and the confidence intervals of risk estimates are wide.     

Hemoglobin glycation index predicts cardiovascular disease in people with type 2 diabetes mellitus: A 10-year longitudinal cohort study

Background and aims

Previous studies have suggested that the hemoglobin glycation index (HGI) can be used as a predictor of diabetes-related complications. We examined the prognostic significance of a high HGI for cardiovascular disease (CVD) in an ongoing hospital-based cohort.

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

Non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide. NAFLD progresses in some cases to non-alcoholic steatohepatitis (NASH), which is characterized, in addition to liver fat deposition, by hepatocyte ballooning, inflammation and liver fibrosis, and in some cases may lead to hepatocellular carcinoma. NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus (T2DM). Currently, lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in the management of T2DM and do not have major side effects like hypoglycemia. In patients with NAFLD, the GLP-1 receptor production is down-regulated. Recently, several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation, alleviating the inflammatory environment and preventing NAFLD progression to NASH. In this review, we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH. Finally, as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD, we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.     

Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women

Background

Hemoglobin A1c (HbA1c) is a marker of cumulative glycemic exposure over the preceding 2- to 3-month period. Whether mild elevations of this biomarker provide prognostic information for development of clinically evident type 2 diabetes and cardiovascular disease among individuals at usual risk for these disorders is uncertain.

Methods

We examined baseline HbA1c levels as a predictor of incident clinical diabetes and cardiovascular disease (nonfatal myocardial infarction, coronary revascularization procedure, ischemic stroke, or death from cardiovascular causes) in a prospective cohort study beginning in 1992 of 26,563 US female health professionals aged 45 years or more without diagnosed diabetes or vascular disease (median follow-up 10.1 years).

Results

During follow-up, 1238 cases of diabetes and 684 cardiovascular events occurred. In age-adjusted analyses using quintiles of HbA1c, a risk gradient was observed for both incident diabetes and cardiovascular disease. After multivariable adjustment, HbA1c remained a strong predictor of diabetes but was no longer significantly associated with incident cardiovascular disease. In analyses of threshold effects, adjusted relative risks for incident diabetes in HbA1c categories of less than 5.0%, 5.0% to 5.4%, 5.5% to 5.9%, 6.0% to 6.4%, 6.5% to 6.9%, and 7.0% or more were 1.0, 2.9, 12.1, 29.3, 28.2, and 81.2, respectively. Risk associations persisted after additional adjustment for C-reactive protein and after excluding individuals developing diabetes within 2 and 5 years of follow-up.

Conclusions

These prospective findings suggest that HbA1c levels are elevated well in advance of the clinical development of type 2 diabetes, supporting recent recommendations for lowering of diagnostic thresholds for glucose metabolic disorders. In contrast, the association of HbA1c with incident cardiovascular events is modest and largely attributable to coexistent traditional risk factors.     

糖化血红蛋白A1c在糖尿病监测和诊断中的应用

近年来,糖化血红蛋白(Hb)A1c在糖尿病监测和诊断中的应用方面有许多进展,主要包括:(1)其测定的标准化.(2)估计的平均血糖概念的提出,其与HbA1c的转换关系及其在糖尿病监测中的作用.(3)提出以HbA1c≥6.5%作为糖尿病诊断标准.但因HbA1c的测定受众多因素影响,且其与糖尿病并发症的关系尚未有定论,将Hb...     

Optimal hemoglobin A1C cutoff value for diabetes mellitus and pre-diabetes in Pudong New Area,Shanghai, China

Aims

Due to the diversity of the Chinese population, it requires considerable research to evaluate HbA1c diagnostic threshold for diagnosis of hyperglycemia.

中国城市中心医院糖尿病健康管理调查

目的　调查中国城市市级中心医院糖尿病控制管理和晚期并发症的状况。方法　在中国49家市级中心医院连续选取治疗一年以上的 2 2 48例糖尿病患者 ,通过回顾病历 ,门诊访谈 ,开展回顾 前瞻的大型调查 ,以收集患者的人口学资料、糖尿病类型及相关治疗、血糖控制及并发症、心血管危险因素和肾功能等资料 ,并采集指血在中心实验室以高压液相色谱法检测HbA1c。结果　入选的 2 2 48例患者年龄为 (61.3± 11.1)岁 ,发病年龄为 (5 2 .8± 11.1)岁 ,其中大部分 (97% )为 2型糖尿病患者。研究人群HbA1c为(7.7± 1.7) % ,2 5 .9%的患者血糖控制理想 (HbA1c<6.5 % )。 41.7%的患者在家中进行血糖自我或尿糖监测。平时作饮食控制和体育锻炼的患者分别为 72 .7%和 5 8.6%。发生率最高的并发症为神经病变 (3 6.2 % ) ,其次为白内障 (3 2 .2 % )和背景性视网膜病变 (2 3 .2 % )。多数 2型糖尿病患者 (62 .0 % )为超重 (BMI≥2 3kg/m2 )。结论　仅有 2 5 .9%的糖尿病患者血糖控制理想 ,因此 ,市级中心医院的糖尿病治疗和管理水平有必要进一步提高 ,包括大力宣传健康的生活方式和血糖自我监测的重要性 ,推广强化治疗 ,以期预防晚期并发症发生     

Diabetes mellitus defined by hemoglobin A1c value: Risk characterization for incidence among Japanese subjects in the JPHC Diabetes Study

Aims/Introduction: Although several risk factors for type 2 diabetes have been identified, most of them have been identified in studies on Western populations, and they should be evaluated in a Japanese population. In 2010, new diagnostic criteria for diabetes mellitus using hemoglobin A1c (HbA_1c) were released and its use in epidemiological studies has many advantages. The aim of the present study was to evaluate risk factors for type 2 diabetes defined based on HbA_1c values in a Japanese population. Materials and Methods: A total of 9223 subjects (3076 men and 6147 women) were followed up for 5 years. Diabetes was defined based on self‐report or HbA_1c value. Risk factors for diabetes were evaluated as odds ratios adjusted for potential confounding factors by logistic regression. Results: During the 5‐year follow‐up period, we documented 518 incident cases of diabetes (232 men and 286 women). Of the 518 incident cases, 310 cases were diagnosed by HbA_1c alone. Among the men, age, smoking (both past smoking and current smoking) and family history of diabetes significantly increased the risk of diabetes. Among the women, body mass index, family history of diabetes and hypertension significantly increased the risk of diabetes. These results did not change markedly after adjustment for the baseline HbA_1c values, and the baseline HbA_1c value itself was a significant risk factor for diabetes mellitus. Conclusions: Known risk factors for diabetes established in Western populations also increased the risk of diabetes in a Japanese population defined on the basis of HbA_1c values. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00119.x, 2011)     

Impact of Glucagon-like peptide 1 receptor agonists on peripheral arterial disease in people with diabetes mellitus: A narrative review

Peripheral arterial disease (PAD) is a common macrovascular complication of diabetes mellitus (DM). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are among the latest class of antidiabetic medications that stimulate insulin synthesis and secretion and have been used for the management of type 2 DM. Apart from the effect on glycaemic control, GLP-1RAs also have a robust impact on weight reduction and have shown favorable effects on cardiovascular morbidity and mortality in cardiovascular outcome trials (CVOTs). The aim of this review was to examine the impact of GLP1-RAs on PAD among people with DM based on CVOTs, randomized controlled trials, observational studies as well as systematic reviews and meta-analyses. Data from retrospective studies and meta-analyses have shown superiority of these agents in comparison with other antidiabetic medications such as sodium-glucose cotransporter type 2 inhibitors and dipeptidyl peptidase-4 inhibitors in terms of PAD-related events. Nevertheless, data from CVOTs regarding the impact of GLP-1RAs on PAD are scarce and hence, safe conclusions regarding their effects cannot be drawn. Further prospective studies are needed to examine the impact of GLP-1RAs on PAD-related incidents including major adverse limb events, lower limb amputations and revascularization procedures.     

Discordance between fasting glucose-based and hemoglobin A1c-based diagnosis of diabetes mellitus in Koreans

We analyzed data of 35,624 non-diabetic Koreans using fasting plasma glucose (FPG) criteria and HbA1c criteria in screening for diabetes. Among the 1,491 subjects newly diagnosed with diabetes, 473 (31.6%) met the FPG criteria only (≥7.0 mmol/l), 350 (23.5%) met HbA1c criteria only (≥6.5%), and 668 (44.9%) met both criteria. The DM-by-HbA1c group had significantly older age, higher proportion of women, and lower hemoglobin concentration. The DM-by-FPG group had higher systolic and diastolic blood pressure, fasting serum insulin, and HOMA-IR. Further studies are needed to determine which of these criteria is superior in predicting the risks of long-term vascular complications of diabetes.     

糖化血红蛋白的临床应用进展

美国糖尿病协会(ADA)和世界卫生组织(WHO)正式推荐糖化血红蛋白(HbA1c)作为糖尿病的诊断标准之一,国内关于HbA1c检测方法的标准化及其筛查、诊断糖尿病前期和糖尿病切点等问题仍存在争议。该文就HbA1c的检测方法标准化及其临床应用等作一综述。     

Glucagon‐like peptide‐1 receptor agonists for type 2 diabetes: A rational drug development

Today, glucagon‐like peptide‐1 (GLP‐1) receptor agonists are established glucose‐lowering drugs used in the management of type 2 diabetes. Their development emerged from the understanding that a combined islet dysfunction comprising of impaired insulin secretion and exaggerated glucagon secretion is the key defect of hyperglycemia. GLP‐1 was shown to target these defects, and after the discovery that dipeptidyl peptidase‐4 inactivates native GLP‐1, several different dipeptidyl peptidase‐4‐resistant GLP‐1 receptor agonists have been developed. They are administered subcutaneously, but show differences in molecular structure, molecular size and pharmacokinetics, the latter allowing twice‐daily, once‐daily or once‐weekly administration. They have been shown to be efficient in reducing both glycated hemoglobin and bodyweight, and to be safe and highly tolerable. Cardiovascular outcomes trials have shown them to be neutral or beneficial. GLP‐1 receptor agonists are positioned as add‐ons to metformin alone or in combination with oral agents in the clinical paradigm. They are also efficient when combined with insulin, and fixed dose combinations with long‐acting insulin have been developed. Recent development includes a very long administration schedule and oral availability. The research from the first demonstration of the antidiabetic action of GLP‐1 in the early 1990s to the enormously accumulated data today represents a successful and rational development, which has been characterized by focused perseverance to establish this therapy in the management of type 2 diabetes.     

GLP-1受体激动剂与二肽基肽酶4抑制剂治疗2型糖尿病的比较

随着对肠促胰素在维持葡萄糖稳定作用认识的日益增多,促进了针对2型糖尿病患者肠促胰素活性缺乏治疗药物的研发.根据肠促胰素治疗药物不同的作用机制,可分为以下2类:(1)胰升糖素样肽1(GLP-1)受体激动剂,包括利拉鲁肽(liraglutide)、艾塞那肽每日2次制剂和艾塞那肽每周1次制剂;(2)二肽基肽酶4(DPP-4)抑制剂,包括西格列汀(sitagliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)和维格列汀(vildagliptin),DPP-4抑制剂可限制内源性GLP-1的降解.这2类药物具有某些共性,如葡萄糖依赖性刺激胰岛素分泌,低血糖发生率低.然而这2类药物在疗效方面的表现却有所不同.本文综述了这2类基于肠促胰素治疗药物的药代动力学及其临床方面的疗效和安全性,阐明了此类药物在2型糖尿病治疗中的地位.