Cardiac implications of hypoglycaemia in patients with diabetes – a systematic review

An electronic literature search of PubMed up to November 2012 was performed using a combination of subject headings and free text incorporating “hypoglycaemia”, “cardiac OR heart”, “QTc”, “arrhythmia”, “endothelium”, “thrombosis”, “inflammation”, “atherosclerosis”, “heart rate”, “heart failure”, “myocardial ischemia”, “myocardial infarction”, “coronary heart disease”, and “angina”. The search was then extended by manually screening the reference lists of included papers.

Identified sources where evaluated according to the PRISMA statement for reporting systematic reviews and meta-analyses of studies [19]. Papers were first subdivided based on whether they were clinical trials involving glycaemic control or studies related to the underlying pathophysiologic mechanisms linking hypoglycaemia with CV risk. Included clinical studies fulfilled all of the following criteria: (1) published as a primary research paper in a peer-reviewed journal; (2) included cohorts of patients with T1D or T2D under intensive glucose-lowering therapy; and (3) reporting the proportion of patients presenting with CV complications. Studies of only highly selected groups (e.g. undergoing cardiac surgery or case reports), and conference proceedings were excluded. Included mechanistic studies fulfilled the following criteria: (1) published as a primary research paper in a peer-reviewed journal, and (2) investigated direct mechanistic links between hypoglycaemia-induced physiologic effects and CV risk. Only papers in English were selected. One reviewer performed the search and screened the titles and abstracts to exclude irrelevant papers. Full-text articles were then reviewed by at least two reviewers to assess eligibility, and consensus was sought to resolve any disagreement between researchers.

We applied the Critical Appraisal Skills Programme guidelines for quality assessment and excluded studies with major limitations in methods or reporting [20]. In addition, the quality of each included study was rated high, moderate or low according to pre-specified markers of quality (Table 1).

Characteristics of included studies were extracted independently by two researchers using a standardised form. These included study design, population, treatments, and CV outcome. A qualitative analysis of the texts was performed.

The most common cause of death in diabetes is CV disease (CVD) [1, 2], and there exists a bulk of evidence that hypoglycaemia is a serious CV risk factor [4, 5]. Six high quality studies have examined CV outcome while comparing intensive glucose-lowering treatment with conventional therapy (Figure 1 & Table 2).

The Diabetes Control and Complications Trial (DCCT), analysing 1,441 T1D patients [39], observed increased hypoglycaemia rates with intensive therapy (insulin pump or three or more insulin injections per day). The trial initially found no effects on CVD, but in a follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a delayed benefit was described [40].

Similar to these data the United Kingdom Prospective Diabetes Study (UKPDS), which enrolled 5,102 newly diagnosed T2D patients [41, 42], found no significant reduction in CV complications and higher rates of severe hypoglycaemia with intensive therapy. However, a 10-year follow-up identified modest post-trial risk reductions [42], again suggesting a delayed benefit. More recently, the ACCORD trial studied 10,252 T2D patients with existing CVD and/or CV risk factors [8], but the trial was interrupted due to excess mortality with intensive treatment. While the rate of hypoglycaemia again grew with intensive therapy, post-analysis of the study concluded that it did not account for the rise in mortality rate [43, 44]; however, it is difficult to exclude the contribution of hypoglycaemia [37]. In contrast, the ADVANCE study, which analysed 11,140 T2D patients [9], did not observe increased mortality. However, intensive therapy again led to hypoglycaemia, which was linked to vascular events and CV-related death [6]. Also, when 1,791 military veterans with poorly controlled T2D were studied in the VADT [45], intensive therapy-related hypoglycaemia with no CV benefit was again observed.

ORIGIN (Outcome Reduction With Initial Glargine Intervention) [47] was somewhat different from the aforementioned trials in that it included patients with type 2 diabetes but also patients with pre-diabetes but high cardiovascular risk. At an almost identical HbA1c (ORIGIN 6.2%, ACCORD 6.4%) severe hypoglycemia was infrequent in the glargine arm of ORIGIN but much more frequent in the intensified treatment arms of ACCORD (3.1%) and VADT (3.8%). This has to be interpreted however on the background of a longer diabetes duration (10 years in ACCORD and 11.5 years in VADT vs. 5 yrs in ORIGIN) and high baseline HbA1c values (8.1% in ACCORD, 9.4% in VADT vs. 6.4% in ORIGIN).

Therefore, while these studies collectively showed no CV-related benefit, it was evident that intensive therapy increased hypoglycaemia, suggesting that it might represent a barrier for treatment. Thus, investigations have begun to unravel the complex mechanistic relationship between hypoglycaemia and the CV system.

Our search resulted in 572 studies identifying specific hypoglycaemia-induced pathophysiological changes that might drive CV risk in diabetes, of which 484 were excluded based on relevance and quality (Figure 1 & Table 3). Based on these findings, we will discuss the key hypoglycaemia-mediated risk factors that are currently thought to promote CVD.

Although there is some evidence to support a CV protective role for insulin treatment [84] there are many studies indicating that insulin might be a double-edged sword with regard to CV health because of its associated risk of inducing hypoglycaemia [6, 13, 45]. For this reason, studies have begun to compare various antidiabetic treatments for their relative likelihood to induce hypoglycaemia in T1D and T2D. The U.K. Hypoglycaemia Study Group found that mild hypoglycaemia in T2D patients during early insulin use was considerably less frequent than in T1D. Also, there was no difference in the proportion of patients with T2D experiencing severe hypoglycaemia after treatment with sulfonylurea compared to insulin [7], while metformin was associated with a lower risk for hypoglycaemia compared with conventional therapy with sulfonylurea or insulin. ORIGIN on the other hand provided evidence that insulin initiated early in the course of type-2 diabetes does not generally increased of hypoglycaemia [47]. Generally sulfonylurea are perceived to be associated with increased cardiovascular risk [85]. Interestingly, it was demonstrated that a specific sulfonylurea, glibenclamide (also known as glyburide), was associated with a lower risk of CV complications compared to treatment using metformin (belonging to the biguanide class) or rosiglitazone (thiazolidinedione class) in T2D [86]. However, at the same time, fewer patients in the rosiglitazone-treated group displayed hypoglycaemia compared to the glibenclamide-treated patients [86]. Overall these findings regarding increased risk of hypoglycaemia with use of insulin and sulfonylureas were verified in a recent systematic review of the literature, which compared these two conventional treatments with metformin, pioglitazone, alpha-glucosidase inhibitors, incretin mimetics (DPP4-Inhibitors, GLP1-analogues), and bile acid sequestrants during treatment of T2D [87]. Particularly, there has been recent discussion regarding incretin-based therapies and their potential benefit in regard to the risk for hypoglycaemia and CVD; however, more research is required [88‐90].

Recent results from comprehensive clinical trials, which demonstrated increased rates of hypoglycaemia with intensive diabetes therapy, have added to the uncertainty surrounding the role of hypoglycaemia in CVD, but at the same time have encouraged scientists to more thoroughly investigate the potential mechanistic impact of hypoglycaemia in CV risk. So far, studies indicate that hypoglycaemia increases CV dysfunction through many risk factors (Table 3), including increased thrombotic tendency, abnormal cardiac repolarization, inflammation, and development of atherosclerosis. These hypoglycaemia-associated risk factors contribute to events such as arrhythmia, silent myocardial ischemia/angina, myocardial infarction, and stroke during diabetes.

Major strengths of recent large clinical trials investigating the role of hypoglycaemia in CVD include access to large patient cohorts in multi-centre studies, as well as the ability to do long-term follow-ups and retrospective studies. However, one major limitation of these trials is the inability to assign the cause of death with certainty to hypoglycaemia. In many cases hypoglycaemia is asymptomatic, which means that it can be challenging to assess its contribution to CV complications during diabetes. This ambiguity has been a barrier to assessing and analysing patient data during these investigations.

Related to mechanistic studies, a major strength is that hypoglycaemic responses can be induced in healthy subjects, which are a very useful tool for examining the diverse effects of acute hypoglycaemia. Moreover, these results can then be easily compared with diabetic individuals. The major limitation of the mechanistic research described here is that, for the most part, it consists of observational studies. Thus, factors that are altered during hypoglycaemia (i.e. cytokines, thrombotic factors, etc.) have not been concretely demonstrated to contribute directly to hypoglycaemia-mediated CV dysfunction in diabetes. More study will be required to ascertain which factors are the most important in this regard, and whether there is truly a combinatorial effect that drives CVD.

From the studies analysed here, the most obvious discrepancies occurred within the results of the major clinical trials. For example, the significant increase in death associated with intensive therapy of patients with existing CVD and/or CV risk in the ACCORD trial was not observed in the other studies [8]. Moreover, the ACCORD investigators could not ascertain the underlying cause for this difference in mortality [43, 44]. In fact, only the ADVANCE trial was able to see a clear association of hypoglycaemia with increased risk for macrovascular events and CV-related death [6]. Thus, it remains plausible that hypoglycaemia could have influenced the results observed in the ACCORD trial since it is difficult to reliably assign the potential contribution of hypoglycaemia to these deaths. Additionally, although slight CV benefit was observed in some of these trials, overall it was not significant, and it is possible that the true advantages of intensive therapy will not be noted until much later as suggested by the UKPDS and DCCT/EDIC trials [40, 42]. Finally, it is interesting that the observed rates of hypoglycaemia were variable; yet, it seems undeniable that collectively the data reveal significantly increased episodes of severe hypoglycaemia with intensive treatment. Thus, even though there are some discrepancies between these trials, the overall findings support the necessity for a more thorough understanding of the effects of this common complication in diabetes.

There are several questions and future implications that arise from this work. For example, hypoglycaemia is known to be a regular event for insulin-requiring diabetic patients; however, if hypoglycaemia is strongly linked to CV risk, then it remains unclear why many patients do not show CV problems after repeated exposure to hypoglycaemic episodes. The determining factors for this might include genetic traits, which could be identified through future investigation. Moreover, there has been some debate over whether hypoglycaemia is simply a marker of vulnerability for CVD or a cause for it [6], which will only be resolved through continued research regarding the potential direct mechanistic roles of hypoglycaemia in CVD. Future studies using techniques such as CGM will hopefully continue to shed light on the potential contributions of hypoglycaemia to CVD. Additionally, the fact that delayed CV benefit was reported following intensive diabetes therapy is an intriguing result that warrants more study [40, 42]. Also, because hypoglycaemia has potentially life-threatening effects for diabetes patients, the continued characterization of antidiabetic treatments that have reduced risk for causing hypoglycaemia is essential for the management of diabetes. These drugs could then be utilized in future trials to establish whether hypoglycaemia is truly a barrier to benefit during intensive therapy.