MYOCARDIAL ISCHEMIA, INFARCTION, AND ARRHYTHMIAS
The earliest study in 1932 reported chest pain consistent with myocardial ischemia in two of seven type 1 diabetic patients with known cardiovascular disease (19). However, other similar studies failed to confirm these findings (3,5). More recently, in a retrospective review of 14,670 patients with coronary artery disease, recruited for the Bezafibrate Infarction Prevention study (a secondary prevention prospective multicenter randomized placebo-controlled double-blind trial conducted to assess the efficacy of bezafibrate in reduction of coronary events conducted in Israel) over an 8-year mean follow-up, hypoglycemia (<70 mg/dl) was a predictor of increased all-cause mortality with a hazard ratio of 1.84, but not of increased coronary artery disease mortality (4). The Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes showed that more cardiac events were documented in patients after institution of intensive glycemic control versus standard control (32 vs. 20%) (20). However, this was not significantly different, since the study was inadequately powered to study this question (20). In contrast, in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%), major cardiovascular events were not significantly different (21).
A few studies using continuous electrocardiogram monitoring and glucose monitoring have been performed recently. Desouza et al. (22) demonstrated that of 54 episodes of hypoglycemia, 10 were associated with symptoms or electrocardiogram evidence of ischemia, whereas only one episode of chest pain occurred during 59 episodes of hyperglycemia. Less studied is the “dead-in-bed” syndrome, which is defined as sudden nocturnal death in type 1 diabetes. In one study, 24 deaths of patients with type 1 diabetes under the age of 50 years were studied (23). Two patients had irreversible hypoglycemic brain damage and died after artificial ventilation. Nineteen others were sleeping alone at the time of death, and 20 were found lying undisturbed (23). Gill et al. (24) demonstrated that, in patients with type 1 diabetes, severe hypoglycemia was associated with a prolonged corrected QT interval. Eight of those episodes also showed cardiac rate and rhythm abnormalities.
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CEREBRAL ISCHEMIA, STROKE, AND DEMENTIA
Severe hypoglycemia has been known to induce focal neurological deficits and transient ischemic attacks, which are reversible with the correction of blood glucose. However, the question whether hypoglycemia increases the risk for stroke or dementia remains controversial. Recent evidence suggests that recurrent or severe hypoglycemia may predispose to long-term cognitive dysfunction and dementia. Whitmer et al. (25) conducted a longitudinal cohort study of 16,667 patients with type 2 diabetes looking at the relationship between hypoglycemia and dementia. The study found that the attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.4% per year. Patients with multiple episodes of hypoglycemia had a graded increase in dementia risk (25). Conversely, severe cognitive dysfunction has been associated with increased risk of hypoglycemia. In the ADVANCE trial (type 2 diabetes), severe cognitive dysfunction increased the risk of severe hypoglycemia (hazard ratio 2.1) in patients with type 2 diabetes (26). The Fremantle diabetes study (type 2 diabetes) found that dementia was a risk factor for hypoglycemia. However, hypoglycemia itself was not found to increase the risk of getting dementia (27). In type 1 diabetes, some small studies show alterations in regional cerebral blood flow in patients with severe hypoglycemia; however, these are temporary and reversible (28).
In the DCCT, despite frequent hypoglycemia, intensively treated patients with type 1 diabetes did not experience cognitive decline. Some small studies show alterations in regional cerebral blood flow in patients with type 1 diabetes with severe hypoglycemia; however, these are temporary and reversible (28). It is unclear whether this finding can be extrapolated to type 2 diabetes. Thus, the role of hypoglycemia in increasing the risk for dementia is still controversial.
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ROLE OF HYPOGLYCEMIA IN THE RESULTS OF RECENT CLINICAL TRIALS
Recently, several large randomized trials evaluating the effects of glycemic control on cardiovascular events have published their results (29–31).
The ACCORD trial randomized 10,251 participants with a history of cardiovascular events or significant cardiovascular risk to a strategy of intensive glycemic control or standard glycemic control (29). The ACCORD trial was halted because of a significant increase in all-cause mortality (22%) and cardiovascular mortality (35%) in the intensive treatment group. In both the intensive and standard treatment arms, participants with severe hypoglycemia had a higher mortality rate than those without severe hypoglycemia (29). However, the association between hypoglycemia and mortality is much more complex in this study. The relative risk of death associated with severe hypoglycemia was 1.28 for the intensive arm versus 2.87 for the standard arm in spite of larger number of severe hypoglycemic episodes in the intensive arm. This suggests that severe hypoglycemia in a certain subset of patients may be associated with mortality rather than the strategy of treatment used (intensive versus standard). However, these data are based on post hoc analysis, and the true cause of the increased mortality in these patients may never become obvious. The subset of patients most prone to the detrimental effects of hypoglycemia had several of the following characteristics: they were likely to be women, African American, older patients, or patients with a longer duration of diabetes and have higher A1C and high albumin-to-creatinine ratio.
VADT randomized 1,791 patients with type 2 diabetes to an intensive treatment group and a conventional treatment group (31). At the end of the study, there was no significant difference in cardiovascular events between the two treatment arms. As expected, there was an increased incidence of severe hypoglycemia in the intensive treatment group. Predictors for hypoglycemia included increased duration of diabetes, insulin treatment at baseline, low BMI, previous cardiovascular events, and high albumin-to-creatinine ratio.
The ADVANCE study randomized 11,140 participants to an intensive glycemic control arm and a standard glycemic control arm (30). Although there was an increased risk of hypoglycemia in the intensive treatment arm, there was no association between hypoglycemia and cardiovascular mortality (30). One explanation for the discrepancy between this finding and that in the ACCORD study is the extremely low number of patients (<3%) who had severe hypoglycemia in the intensive treatment arm, during the course of the entire trial.
It is therefore important to seek out the similarities and differences in the study design and patient population of these studies. Patients in the ADVANCE trial had a 2- to 3-year shorter duration of diabetes as well as a lower baseline A1C than patients in the ACCORD trial. The number of patients on insulin in the intensive arm versus the standard arm was 77 versus 55% in the ACCORD trail, 90 versus 74% in the VADT, and 41 versus 24% in the ADVANCE trial. Thus, the ADVANCE trial had a much smaller proportion of patients on insulin than ACCORD or VADT. This could in part account for the low level of hypoglycemia seen in the intensive arm of the ADVANCE trial (<3%) versus the ACCORD trail (16%) and VADT (21%). The DCCT enrolled type 1 diabetic patients on insulin treatment. In contrast to the UK Diabetes Prospective Study, VADT, and ACCORD, the DCCT had a relatively high risk for severe hypoglycemia in the “conventional” treatment group (0.19 episodes/patient-year) and a threefold increased risk in the “intensive” group (0.62 episodes/patient-year). Interestingly, the more frequent severe hypoglycemia in the intensive group was not associated with increased cardiovascular mortality (13) at later follow-up (1). This indirectly highlights the different cardiovascular risk of hypoglycemia in type 2 versus type 1 diabetes. Thus, it is clear that these trials had different treatment strategies to achieve risk factor modification. Perhaps we can now appreciate that the strategy used to achieve risk factor modification is important in how it affects patient outcomes. Moreover, the particular strategy's effect on a risk factor may not predict its effect on patient outcomes (32).
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