糖尿病人严重心血管事件—低血糖的作用
2012-05-09 11:37:31   来源： 丁香园   作者：  评论：0 点击：

糖尿病人严重心血管事件—低血糖的作用

 
Serious Cardiovascular Outcomes in Diabetes
The Role of Hypoglycemia
 
Natalia Yakubovich, MSc, MD; Hertzel C. Gerstein, MD, MSc
Hypoglycemia is a well-recognized side effect of glucoselowering therapies in patients with diabetes mellitus. The incidence of mild self-reported hypoglycemic episodes in patients with type 1 diabetes mellitus is approximately 30 episodes per patient per year, whereas the incidence of severe hypoglycemic episodes (ie, those that require third-party assistance) may be as high as 3.2 episodes per patient per year.1–3 Hypoglycemic episodes occur much less frequently in patients with type 2 diabetes mellitus, in whom the
incidence of mild and severe hypoglycemic episodes is 2 to 10 per patient per year and 0.1 to 0.7 per patient per year, respectively.2
低血糖是糖尿病病人治疗过程中常见的副作用。对于1型糖尿糖患者，能自我识别的轻微发作每年每个患者可高达30次左右，而需要第三者帮助才能处理的严重发作每年每个患者可高达3.2次左右。对于2型糖尿病患者，轻微发作约2-10次左右、严重发作为0.1-0.7 /每年每个患者。
When patients are alerted to the occurrence of a hypoglycemic episode by symptoms such as tremor, diaphoresis, tachycardia, malaise, hunger, and anxiety, they can abort these episodes by consuming carbohydrates. However, if hypoglycemic episodes occur rapidly or are unrecognized and untreated, the resulting neuroglycopenia may cause confusion, seizures, accidents, angina, and, rarely, death or permanent cognitive impairment.3,4 Patients who experience frequent episodes of hypoglycemia are especially at risk of having unrecognized hypoglycemic episodes (and their sequelae), because their counterregulatory response to hypoglycemia becomes blunted. Indeed, the rare occurrence of sudden death during sleep in young patients with type 1 diabetes mellitus (the so-called dead-in-bed syndrome) has been attributed to hypoglycemia, although this cause is seldom proven.5–7
如果患者能对相关症状（如：震颤、出汗、心动过速、全身乏力、饥饿和焦虑）警觉，服用碳水化合物可终止这种发作。然而，当低血糖发作出现迅速或未被患者识别与处理，造成神经低血糖症可引发意识模糊、牙关紧闭、意外伤害、绞痛与罕见的死亡和永久性的认知障碍。如果患者经常出现低血糖发作，因其对低血糖的抗调节反应出现迟钝，特别容易出现对发作与伴随症状的认知下降。其实对于年青1型糖尿病患者出现罕见的睡眠中猝死，也被认为与低血糖有关，虽然这种原因极少得到证明。
It is well known that hypoglycemic episodes are associated with a surge of sympathetic activity and a release of catecholamines. 8–10 These observations have supported the suggestion that the tachycardia and the rise in blood pressure observed during a hypoglycemic episode might destabilize an atherosclerotic plaque.11 These hemodynamic changes, the increased myocardial work, and hypoglycemia-induced increases in platelet aggregation, platelet activity,12–14 and hematocrit15,16 may precipitate cardiac and cerebral ischemic events in patients at high risk of cardiovascular disease.17Support for this possibility comes from a number of small studies and case reports. For example, continuous glucose and ECG monitoring in 19 patients with coronary artery disease and type 2 diabetes mellitus18 revealed a higher frequency of ischemic ECG changes when glucose levels fell below 3.9 mmol/L (70 mg/dL). A similar study in 24 patients with type 1 diabetes mellitus19 revealed a nocturnal increase in the corrected QT interval and some minor rhythm disturbances when nocturnal glucose levels fell below 3.5 mmol/L (63 mg/dL) that were not observed when nocturnal glucose levels were _5 mmol/L (90 mg/dL). Experimentally induced hypoglycemia prolonged the corrected QT interval and reduced potassium levels in healthy adults10 and in people with type 1 and type 2 diabetes mellitus.20,21 Finally, case reports have shown a relationship between ischemic cerebral changes and concurrent severe hypoglycemia in patients presenting with neurological deficits22,23 and between arrhythmias and concurrent low blood glucose levels that responded to glucose administration.24,25
我们已知道低血糖发作引发交感神经活动与儿茶酚胺释放的暴发，这会引起心动过速及血压升高造成斑块的不稳定性。这种血流动力学的不稳定、心肌作功的增加与低血糖会增加血小板的聚集与激活、红细胞压积的升高，进而在心血管病高危患者引起心脏或颅内的缺血性事件。支持这种理论依据主要来源来一系列小规模的临床试验与个案报道，例如对19例冠心病并2型糖尿病患者持续血糖与心电监测表明：当血糖水平降致5mmol/L(90mg/dL)水平时心电图心肌缺血的频度明显增加。在健康与糖尿病人（1型与2型）中试验性诱导低血糖可延长校正的QT间期及降低血钾。最后，个案报道表明有神经功能障碍的患者脑的缺血性变化与严重的低血糖明显相关，心率失常与服用葡萄糖仍有低血糖状况相关。
These considerations clearly provide the basis for concerns that hypoglycemic episodes may promote cardiovascular events (myocardial infarction [MI], stroke, and cardiovascular death) and death. These concerns are magnified by the fact that hospitalized and ambulatory individuals with diabetes may have concomitant renal disease, liver disease, weight loss, or other conditions that increase the likelihood of having a hypoglycemic episode and that are themselves risk factors for serious health outcomes. If hypoglycemic episodes precipitate (rather than are simply associated with) cardiovascular events and death, then epidemiological studies would identify hypoglycemia as an independent risk factor for serious cardiovascular outcomes, and interventions that increase the risk of hypoglycemia might increase the risk of these outcomes. The recent publication of several large randomized trials and epidemiological studies that were restricted to people with diabetes and that collected and reported data regarding both hypoglycemia and serious outcomes provides an opportunity to examine this possibility. These studies are reviewed and summarized below so as to address the following questions:
1. Does an intervention that increases the risk of hypoglycemic episodes increase the risk of serious cardiovascular outcomes?
2. Are hypoglycemic episodes a risk factor for serious cardiovascular outcomes?
3. Do hypoglycemic episodes precipitate serious cardiovascular events?
所有这些均清楚表明：低血糖发作可能会促进心血管事件（心肌梗塞、中风与心血管死亡）与死亡。这种担心在糖尿病同时并发肾脏疾病、肝脏疾病、消瘦和其它严重健康问题更易发作低血糖的住院或活动不便的患者会升高。如果低血糖发作促发（而不仅仅是相关）心血管事件与死亡，那么流行病学研究应当能认别低血糖是作为严重心血管事件的独立危险因子，增加低血糖发作风险的干预应当能增加这些事件风险。最近一系列糖尿病大规模随机临床试验与流行病学调查，收集与整理了关于低血糖与严重事件的数据，为检验这种可能性提供了机会。这些研究的综述与概要如下，以便说明下列问题：
1、   增加低血糖发作风险的处理是否也能增加严重心血管事件的风险？
2、   低血糖发作是否是严重心血管事件的危险因素？
3、   低血糖发作能否促发严重的心血管事件？
 
增加低血糖发作风险的处理是否也增加严重心血管事件发作的风险？
 
Does an Intervention That Increases the Risk of Hypoglycemic Episodes Increase the Risk of Serious Cardiovascular Outcomes?
 
Any effect of hypoglycemia on cardiovascular outcomes may be influenced by a patient’s age, the clinical setting, the glucose-lowering therapies that are used, and the glucose level that is achieved. Several large randomized, controlled trials have assessed the effect of a variety of glucose-lowering approaches on cardiovascular outcomes in ambulatory patients with diabetes. These trials can broadly be classified as trials in which allocation was to 2 different targeted levels of glycemic control (intensive versus standard) and trials in which allocation was to 2 different glucose-lowering strategies, in which differences in glycemic control may have been achieved but were not the focus of the intervention. Several other trials of the effect of insulin therapy on mortality in hospitalized critically ill patients with and without diabetes have also been published. Although these trials defined hypoglycemic events in a variety of ways, they all reported the effect of the allocated therapy on both hypoglycemic events and adjudicated cardiovascular outcomes. These trials therefore provide some insight into the nature of the relationship between hypoglycemia and cardiovascular events.
任何低血糖对心血管事件的影响都可能受到患者的年龄、临床环境降血糖处理方法与达到的血糖水平的影响。数个大规模、随机、对照的临床试验，评估了卧床糖尿病人不同的降糖处理方法对心血管事件的影响，这些处理可大致分为二类不同的血糖控制水平（强化与标准）的处理策略，以达到不同的控制升高的胰岛素水平而不注重具体的措施。而其它的几个临床试验主要是研究对于重症患者（包括糖尿病与非糖尿病患者）应用胰岛素对死亡率的影响。仅管这些试验以不同的方法来定义低血糖事件，但均对不同处理方法对低血糖事件与确定的心血管事件的影响进行了研究。因而这些研究都对深入了解低血糖与心血管事件关系的本质提供了某些证据。
 
比较不同的强度降糖处理的试验
 
Trials Comparing Different Intensities of Glucose-Lowering Therapies
 
To date, 5 large trials allocated people to a strategy that targeted more- versus less-intensive glucose lowering. These included the Diabetes Control and Complications Trial (DCCT),26 which was conducted in relatively young people with type 1 diabetes mellitus, and the United Kingdom Prospective Diabetes Study (UKPDS),27 Action to Control Cardiovascular Risk in Diabetes (ACCORD),28 Veterans Affairs Diabetes Trial (VADT),29 and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)30 trials, which were conducted in people with type 2 diabetes mellitus.                                
目前有5个大规模临床试验来比较强化与常规血糖控制的结果的试验。这些包括“糖尿病控制与并发症的试验（Diabetes Control and Complications Trial-DCCT）”，主要是在年青的1型糖尿病患者中进行的试验；联合王国糖尿病前瞻研究（United Kingdom Prospective Diabetes Study -UKPDS）；在糖尿病控制心血管危险因素行动（Action to Control Cardiovascular Risk in Diabetes -ACCORD）试验；退伍军人协会糖尿病试验（Veterans Affairs Diabetes Trial -VADT)；糖尿病行动与血管疾病—在2型糖尿病进行ADVANCE(Preterax降压药.由2.0毫克培哚普利和0.625毫克吲达帕胺组成and Diamicron Modified Release Controlled达美康控释剂Evaluation ) 试验。
 
1型糖尿病
Type 1 Diabetes Mellitus
 
In the DCCT, 1441 people with a mean duration of type 1diabetes mellitus of 5.7 years and a mean age of 27 yearswere randomly allocated to either intensified insulin therapytargeting a hemoglobin A1c _6.05% or conventional insulintherapy aimed at preventing symptoms of hyperglycemia orhypoglycemia.26 Ninety-nine percent of the participants completedthe active-therapy period of the trial after a meanfollow-up of 6.5 years, and 93% were passively followed upfor an additional 10.5 years. At the end of the active-therapyperiod, the mean hemoglobin A1c levels were 7.4% and 9.1%in the treatment and control groups, respectively.31 Duringthis period, severe hypoglycemic episodes requiring assistanceaffected approximately 27% of participants in theintensive-therapy group and 10% of participants in theconventional group annually.32 Moreover, a very stronginverse relationship was noted between the achieved hemoglobinA1c and the risk of severe hypoglycemia.26 Despitethis much higher risk of severe hypoglycemia, participantswho had been allocated to the intensified insulin therapygroup had a nonsignificant 41% reduction in cardiovascularevents at the end of the active treatment period26 and asignificant 42% (95% confidence interval [CI] 9% to 63%)lower risk of cardiovascular disease than participants whohad been allocated to the conventional insulin therapy groupwhen evaluated after 17 years of follow-up. Furthermore,analyses suggested that the difference in hemoglobin A1cduring the active treatment period accounted for this benefit.31 The risk of cardiovascular events among the people whoexperienced severe hypoglycemia was not reported. Nevertheless,these data suggest that in type 1 diabetes mellitus, aglucose-lowering therapy that dramatically increases the riskof severe hypoglycemia does not cause long-term cardiovascularharm.
在DCCT试验中，1441例1型糖尿病患者，平均发病时间5.7年，平均年龄27岁，随机分为强化胰岛素治疗组（使糖化血红蛋白目标达6.05%）与常规胰岛素治疗组（达到防止高血糖与低血糖症状的目标既可），约有99%的患者完成了平均约6.5年治疗观察期，93%患者继续接受了另外的10.5年的后续观察期。在治疗观察期间，强化组与常规组的糖化血红蛋白水平分别为7.4%与9.1%，在这期间，强化治疗组每年约有27%患者发生了需要外人帮助的严重低血糖发作，而常规组每年约有10%患者。并且严重低血糖与糖化血红蛋白水平之间表现出明显的负相关。仅管在强化治疗组有明显的严重低血糖发作，但在治疗观察期间心血管事件的危险降低了41%与常规组比较无统计学意义。在心血管病风险方面，17年的观察期间强化组下降了42% (95% 可信区间[CI] 9% - 63%)与常规组相比有统计学意义；进一步的分析提示：在观察期间的糖化血红蛋白的水平的不同与受益直接正相关。但对于严重低血糖发作患者的心血管事件的风险未作进一步的报告。尽管如此，对于1型糖尿病患者降糖处理虽明显增加了严重低血糖发作的风险但未造成长期的心血管损害。
 
2型糖尿病
Type 2 Diabetes Mellitus
The 4 trials conducted in people with type 2 diabetes mellitus differed with respect to the participants studied and the approach used (Table 1). The UKPDS was conducted in people with newly diagnosed type 2 diabetes mellitus and relatively low cardiovascular risk; only 2% had a history of preexisting cardiovascular disease.27,33 Conversely, the ACCORD, ADVANCE, and VADT were conducted in people with established diabetes of 10, 8, and 12 years duration, respectively, and with other risk factors for cardiovascular disease. Indeed, 35%, 32%, and 40% of participants in ACCORD, ADVANCE, and VADT had a previous cardiovascular event, respectively.28–30 These trials differed in the approach to glucose lowering. In the UKPDS, the 2 different fasting glucose levels were targeted by allocating people to an intensive glucose control policy that started with insulin or sulfonylurea versus a conventional control policy based on diet, whereas in the ACCORD, ADVANCE, and VADT trials, 2 different levels of hemoglobin A1c were targeted with a similar, broad menu of drugs that were added or adjusted at regular visits. These glycemia intervention strategies achieved median hemoglobin A1c levels that varied from 6.4% to 7.0% in the intensive-therapy groups and from 7.3% to 8.4% in the standard-therapy groups.
在2型糖尿病患者进行的4个临床试验主要在参与者与处理方法上有所区别（见表1）UKPDS试验是在新诊断2型糖尿病与相对低心血管风险的患者中进行的，只有2%患者有心血管病史。相反的，在ACCORD、ADVANCE与VADT试验中，目的是控制糖化血红蛋白的水平在2种不同的水平，而服用药物是一系列大范围的相同药物（根据观察进行增加与调整），这些对高血糖的干预措施所达到的平均糖化血红蛋白水平在强化治疗组为6.4% - 7.0%，常规处理组为7.3% - 8.4%。
 

The effect of the interventions studied in these trials on the risk of severe hypoglycemia during a follow-up period ranging from 3.4 to 5.6 years was recently meta analyzed.33Overall, people who were allocated to the intensive-therapy arm were 2.5 times more likely to experience 1 or more severe hypoglycemic events (95% CI 1.9 to 3.2) than those who were allocated to the standard-therapy arm. Of note was evidence of statistical heterogeneity in the risk of severe hypoglycemia among the trials, with a 1.9-fold higher risk in the intensive- versus standard-therapy group in ADVANCE and a 3-fold higher risk in ACCORD and the UKPDS.33Despite this higher risk of severe hypoglycemia in the intensive-therapy groups in all 4 studies, a meta-analysis of the effect of the intervention on cardiovascular outcomes suggested that an intensive approach modestly reduced the overall risk of the first occurrence of major cardiovascular events, comprising nonfatal MI, nonfatal stroke, or cardiovascular death (hazard ratio [HR] 0.91, 95% CI 0.84 to 0.99). This effect was reflected in a reduced risk of MI (HR 0.85, 95% CI 0.76 to 0.94) but no effect on the risk of stroke (HR 0.96, 95% CI 0.83 to 1.10) or cardiovascular death (HR 1.10, 95% CI 0.84 to 1.42). Moreover, the effect on cardiovascular death varied among studies, with evidence of statistical heterogeneity: Compared with standard therapy, intensive therapy increased the risk of cardiovascular death in the ACCORD trial and had a neutral or salutary effect in the ADVANCE and the UKPDS trials. Despite these differences, these 4 trials suggest that in people with type 2 diabetes mellitus, glucose-lowering approaches that clearly increase the risk of severe hypoglycemia reduce the risk of MI, have a neutral effect on stroke, and have an uncertain and apparently mixed effect on cardiovascular death.
这些试验干预措施（在3.4 - 5.6年期间）发生严重低血糖的风险最近进行了荟萃分析。强化处理组比常规处理组严重低血糖事件多2倍，大多发生1次或多次(95% CI 1.9 to 3.2)事件。更值得注意是这些试验中严重低血糖事件风险的统计学差异，强化处理比常规处理在ADVANCE试验中高1.9倍，而在ACCORD 与UKPDS试验中高3倍。尽管在所有4个试验中，强化处理组的严重低血糖事件风险增加，但干预措施对心血管事件影响的荟萃分析表明强化治疗适度降低了主要心血管事件（包括非致死性心梗、非致死性中风或心血管死亡-危险比[HR] 0.91, 95% CI 0.84 - 0.99）,这种影响主要反应在降低心肌梗塞的风险(HR 0.85, 95% CI 0.76 to 0.94)，但非中风的风险(HR 0.96, 95% CI 0.83 to 1.10)或心血管死亡风险(HR 1.10, 95% CI 0.84 to 1.42)。而且，对心血管死亡线的影响各试验间有所差别，并且有统计学上意义：与常规治疗组相比，在ACCORD试验中强化治疗组增加了心血管死亡的风险，而在ADVANCE与UKPDS试验中的影响是中性或相反的。尽管有这些不同，4个临床试验均表明，在于2型糖尿病患者强化降血糖处理明显增加了严重低血糖分险并降低了心血梗塞的风险，对中风的影响中性，而以心血管原因的死亡影响不能确定与混杂。
 
在2型糖尿病中不同降糖水平比较的试验
Trials Comparing Different Glucose-Lowering Regimens in Type 2 Diabetes Mellitus
The results of 4 large outcomes trials of different glucose lowering approaches or regimens in people with type 2 diabetes mellitus and other cardiovascular risk factors have also been reported and are summarized in Table 1. These included the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE)34; the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD)35; the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes n Patients With Type 2 Diabetes Mellitus (HEART 2D)36; and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D)37 trials. These trials differed
from those described in the preceding section in that they were not designed to achieve a glycemic contrast between the treatment groups. Nevertheless, small differences in both the achieved level of glycemic control and the rates of hypoglycemic episodes were achieved, with hemoglobin A1c levels ranging from 7.0% to 7.7% in the treatment groups and from 7.2% to 7.8% in the control groups[1]
   在表1中亦显示了数个2型糖尿病大规膜临床试验中不同降糖水平与控制范围与心血管危险因素的结果，并进行报告与概述。这些包括：吡格列酮心血管事件的前瞻临床试验(Prospective Pioglitazone Clinical Trial in Macrovascular Events —PROACTIVE)；评介罗格列酮对糖尿病血糖及心血管预后影响试验（Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes —RECORD）；2型糖尿病患者高血糖与其对急性心肌梗塞后心血管预后影响的试验（Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus—HEART2D）；2型糖尿病的旁路血管成形血动重建试验(Bypass Angioplasty Revascularization Investigation 2 Diabetes­—BARI 2D)。与前述试验的主要不同之处是治疗组均未设计采用升胰岛素控制的处理方法。尽管如此，在升胰岛素控制水平和低血糖发作率上获得了稍有差别的结果，糖化血红蛋白水平治疗组为7.0% -7.7%,对照组为7.2% to 7.8%。
                
As noted in Table 1, participants allocated to the treatment group generally had a higher incidence of episodes of severe hypoglycemia than control subjects. Despite these differences, the risk of all-cause death, cardiovascular death, and MI in these trials was not significantly different between the 2 arms. These data again suggest that therapies that increased the risk of hypoglycemia were generally not associated with an increased risk of cardiovascular events.
     如表1中所表示的，治疗组患者通常有较高水平严重低血糖发作率。尽管有这些不同，试验中的全因死亡、心血管死亡和心肌梗塞风险两组间无明显的差异。这些数据再一次证明：低血糖风险的增加通常与心血管事件风险的增加无明显的关联性。
 
血糖代谢异常的重症患者用胰岛素治疗的临床试验
Trials of Insulin Therapy in Critically Ill Patients With Dysglycemia
A recent meta-analysis of 26 trials of insulin therapy and mortality in hospitalized critically ill patients with and without a history of diabetes included 14 trials that provided information on hypoglycemic episodes.38 Despite an overall 6-fold higher risk of hypoglycemic episodes, there was no overall increase in mortality; indeed, studies conducted in surgical intensive care units suggested a reduced mortality. Unfortunately, the risks of hypoglycemia and mortality were not reported specifically for the subgroup of people with diabetes. Nevertheless, these data suggest that an in-hospital intervention that causes hypoglycemic episodes does not increase the risk of mortality.
    最近有一个关于26个有或无糖尿病史的重症患者以胰岛素处理和死亡率的临床试验荟萃分析，其中14个临床试验提供了低血糖发作信息。尽管胰岛素处理使得低血糖发作的风险提高大于6倍，但死亡率并未明显增加；并且在外科ICU病房的数据还提示死亡率有所下降。遗憾的是并未对其中的糖尿病患者进行亚组分析。尽管如此，这些数据表明引起低血糖发作的临床干预并未增加死亡风险。
 
低血糖发作是否是严重心血管事件的危险因子？
Are Hypoglycemic Episodes a Risk Factor for Serious Cardiovascular Outcomes?
Whether hypoglycemia is a risk factor for future cardiovascular events is best assessed by comparing the incidence of serious cardiovascular outcomes in individuals who have had hypoglycemic episodes and in individuals who have not. Several such analyses of data from prospective studies have been reported recently. These analyses were based on people recruited for either epidemiological studies or clinical trials either during a hospitalization or within an ambulatory environment. These studies are consistent with the conclusion that hypoglycemia is indeed a risk factor for cardiovascular outcomes and are summarized below and in Table 2.
低血糖是否是将来心血管事件的危险因子，可通过对有低血糖发作与无低血糖发作患者的严重心血管事件的发生率比较来进行很好的评估。最近有数个前瞻性研究得来的数据分析已经发表，数据分析基于流行病学调查或临床试验（包括住院或非住院）。这些研究均说明低血糖确实是心血管事件的危险因子并且在表2中进行了概述。

住院患者低血糖发作的心血管事件风险
Risk of Cardiovascular Outcomes After an In-Hospital Hypoglycemic Episode Epidemiological Cohort Studies流行病学队列研究
Analyses of the long-term effect of in-hospital hypoglycemic episodes have been based on data collected in single or many hospitals. In 1 study, glucose levels were abstracted from the charts of 684 (96%) of 713 consecutive patients with type 2 diabetes mellitus who were admitted to a Swedish hospital with unstable angina or an acute MI, and the subsequent 2-year mortality outcomes were obtained from the Swedish mortality registry.39 A total of 44 patients (6.4%)experienced at least 1 episode of hypoglycemia, which was defined as blood glucose _3.0 mmol/L (55 mg/dL) with or without clinical symptoms or intervention at any time during hospitalization. These patients were thinner, had a longer duration of diabetes, and were less likely to have a history of hypertension than those who had no hypoglycemic episodes. Moreover, compared with those whose lowest glucose level during the hospitalization was 3.1 to 6.5 mmol/L, they had a higher subsequent 2-year risk of death that persisted after adjustment for the confounders noted above as well as others (HR 1.93, 95% CI 1.18 to 3.17). This mortality risk was similar to that of patients whose lowest in-hospital glucose levels were _6.5 mmol/L. A similar J-shaped relationship between persistently low in-hospital glucose levels _3.9 mmol/L (70 mg/dL) and in-hospital mortality was noted in an administrative database of 16 871 people admitted to the hospital with an acute MI, as well as in the subset of people with a history of diabetes.40
对住院患者低血糖发作的长期影响的分析基于单个或多个医院收集的数据。其中一个研究中，由收入一家瑞典医院2型糖尿病并不稳定性心绞痛与心梗的713例患者中684例(96%)得到血糖水平，并且通过瑞典死亡登记处得到2年死亡事件，其中有44例(6.4%)患者一年中至少发作一次低血糖，诊断标准为血糖≤3.0 mmol/L (55 mg/dL)并在住院期间出现或未出现症状，这此患者与无低血糖发作的患者相比比较偏瘦、患者糖尿病时间较长、而且多有高血压病史，与最低血糖水平在3.1—6.5 mmol/L的患者相比通过对上述所提因素及其它因素进行校正2年死亡风险增高(HR 1.93, 95% CI 1.18 to 3.17)，而且这种死亡风险与住院血糖≥6.5 mmol/L的患者相同。在一个16871例急性心梗的数据库中及有糖尿病病史的亚组中，同样的J形关联可见于持续住院血糖水平≤3.9 mmol/L (70 mg/dL)与住院死亡率之间。
Epidemiological Analyses of Clinical Trials临床试验的流行病学分析
The risk of cardiovascular outcomes after an in-hospital hypoglycemic episode has been analyzed in at least 3 large clinical trials of hospitalized patients. In the 2nd Diabetes, Glucose and Acute Myocardial Infarction (DIGAMI 2) trial,411253 patients with either type 2 diabetes mellitus or an admission blood glucose _11.1 mmol/L who were hospitalized for suspected acute MI were randomized to (1) a 24-hour insulin-glucose infusion aiming at normoglycemia, followed by subcutaneous insulin-based regimen for long-term glucose control; (2) a 24-hour insulin-glucose infusion, followed by standard glycemic care; or (3) standard glycemic care. Participants were hospitalized for approximately 10 days and followed up for a median of 2.1 years after admission. A hypoglycemic episode was defined as blood glucose _3.0 mmol/L, and both symptomatic and nonsymptomatic hypoglycemic episodes were documented during hospitalization. During the first 24 hours of admission, 2.2% of all patients had symptomatic hypoglycemic episodes.43 Regardless of allocated group, individuals who experienced such an episode were generally older and thinner and were more likely to have comorbid conditions than those who did not experience a hypoglycemic episode. Moreover, these individuals were twice as likely to die of all causes (95% CI 1.2 to 3.3) and of cardiovascular causes (95% CI 1.2 to 3.5) during the 2-year follow-up period compared with individuals who did not experience a hypoglycemic episode. It is notable that this increased risk was significantly attenuated after accounting for differences in baseline characteristics between those who did and did not have an episode. Indeed, after adjustment for baseline confounders, the hazard ratio was no longer significant for either total mortality (HR 1.09, 95% CI 0.64 to 1.87) or cardiovascular mortality (HR 1.20, 95% CI 0.69 to 2.09). There was no evidence of an increased hazard of a composite outcome of death, stroke, and reinfarction in the hypoglycemic group in either unadjusted or adjusted analyses.
低血糖发作后的心血管事件风险至少在3个大规模的临床试验中进行了分析。在2型糖尿病、血糖与急性心梗试验（2nd Diabetes, Glucose and Acute Myocardial Infarction —DIGAMI 2）中，1253例有2型糖尿病病史或入院血糖≥11.1 mmol/L 凝有急性心梗的患者，分为（1）头24小时持续胰岛素加葡萄糖注射以达到正常血糖，继续给予皮下注射基础胰岛素量以长期控制血糖；（2）头24小时持续胰岛素加葡萄糖注射，继续给予标准的升胰岛素处理，或（3）标准升胰岛素处理，患者住院起码10天并继续观察平均2.1年,低血糖发作定义为血糖≤3.0 mmol/L ，有症状或无症状低血糖发作均记录于住院病历中。在入院24小时内，约有2.2%患者发作症状性低血糖。不管分在何组，发作低血糖的个体有下列特征，年龄大、体重轻并有合并症；且在2年时间内，低血糖发作者全因死亡率(95% CI 1.2 to 3.3)及心血管死亡率(95% CI 1.2 to 3.5)增加约2倍；更值得注意的是这种死亡风险的增加在考虑了低血糖发作与不发作者之间基础状态不同的因素后会明显减低；实际上，对基础状况进行较正，全因死亡(HR 1.09, 95% CI 0.64 to 1.87)与心血管死亡(HR 1.20, 95% CI 0.69 to 2.09)的风险的差别不再有意义。不管是非进行校正分析，并无证据表明在综合死亡、中风与再梗事件基础上的风险有明显增加。
Similar findings were reported from a combined analysis of data from 2 trials comprising a total of 30 536 patients (5440 with a previous history of diabetes) who were hospitalized with an acute MI. In both of these trials, patients presenting to the hospital with acute ST-elevation MI were randomized to a high-dose glucose-insulin-potassium infusion versus standard care.42 This intervention was aimed at improving energy balance of the ischemic myocardium rather than at lowering plasma glucose. A hypoglycemic episode was defined as a documented glucose value _3.8 mmol/L (70 mg/dL) with or without symptoms of hypoglycemia, and a hyperglycemic episode was defined as a glucose level_7.1 mmol/L (140 mg/dL) without any value _3.8 mmol/L(70 mg/dL). Of the participants with a prior history of diabetes, 0.7% were hypoglycemic at the time of admission, and 2.0% had at least 1 hypoglycemic episode during the first 24 hours after admission. Compared with people whose admission glucose levels were between 3.9 and 7.0 mmol/L, patients whose admission glucose levels were _3.8 mmol/L (70 mg/dL) were twice as likely to die within 30 days of admission (HR 2.13, 95% CI 1.01 to 4.49) after adjustment for confounders. Conversely, hypoglycemic episodes that were detected during the first 24 hours of admission were not related to 30-day mortality after adjustment for confounders (HR 1.58, 95% CI 0.77 to 3.24). Moreover, despite the fact that postadmission hypoglycemia was twice as common in the group allocated to glucose-insulin-potassium, it was not associated with 30-day mortality in either the glucose-insulin potassium group (adjusted HR 0.85, 95% CI 0.59 to 1.24) or the control group (adjusted HR 1.02, 95% CI 0.67 to 1.56). The foregoing analyses therefore suggest that hypoglycemia that spontaneously occurs before hospitalization for coronary disease is a predictor of future mortality. However, they also suggest that hypoglycemia induced by therapy does not increase mortality.
同样的发现可见于包括30536例（其中5440有糖尿病病史）2个大规模临床试验住院急性心肌梗塞合并分析，入院的患者均有ST抬高的急性心肌梗塞，随机分为高剂量的葡萄糖-胰岛素-钾处理组与常规处理组，这种处理的目的关健在于改善缺血心肌的能量平衡而不是血糖的下降，低血糖发作的定义为血糖≤3.8 mmol/L (70 mg/dL) 而不管有无低血糖的症状，而高血糖的定义为≥7.1 mmol/L (140 mg/dL)无仍何低于3.8 mmol/L(70 mg/dL)。对于原有糖尿病病史的患者，约有0.7%入院时有低血糖，入院24小时内约有2.0% 有低血糖发作，与入院时血糖处于3.9- 7.0 mmol/L的患者相比，通过相关因素的校正30天内死亡率(HR 2.13, 95% CI 1.01 to 4.49)增加约有2倍，但入院24小时内低血糖的发作通过较正后与30天内的死亡率(HR 1.58, 95% CI 0.77 to 3.24).无相关性。更明显的是，仅管葡萄糖、胰岛素与补钾组低血糖发作是对照组的2倍, 但30天内的死亡率处理组(adjusted HR 0.85, 95% CI 0.59 to 1.24)与对照组(adjusted HR 1.02, 95% CI 0.67 to 1.56)之间无明显的差别，进一步的分析表明，冠心病患者入院前自然发作的低血糖能作为死亡的预测因素，同时也说明治疗引发的低血糖并不增加死亡率。