Connecting Dots: Hypoglycemia, Cardiovascular Outcomes and All-Cause Mortality
The most important limiting management factor in euglycemic goals in patients with diabetes [Figure 1], is hypoglycemia, "all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm".1 We herein briefly review the manifestations of hypoglycemia with emphasis on severe hypoglycemia, and the controversial relationships to cardiovascular (CV) events (including death).
Figure 1: Manifestations of Hyperglycemia and Hypoglycemia
A blood glucose (BG) ≤ 70 mg/dL is classified as an alert value; a BG <54 mg/dL is clinically significant biochemical hypoglycemia; and severe hypoglycemia is defined as any level associated with severe cognitive impairment requiring external assistance.2 Mild symptoms of hypoglycemia can include, tremor, sweating, hunger, tachycardia, a result of sympathoadrenal and parasympathetic responses, are usually annoying, but well tolerated, but if not managed, can progress to moderate symptoms of anxiety, irritability, confusion, or delirium and to severe hypoglycemia with loss of consciousness, seizure, coma, or even death.
Whether severe hypoglycemia is a 'risk marker' or a 'direct causal effect' for adverse CV outcomes is controversial. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,3 was designed to determine whether a therapeutic strategy targeting A1C levels to a normal goal, i.e. <6.0%, would reduce the rate of CV events, relative to patients with A1C levels ranging 7.0 to 7.9%. The ACCORD patients (n=10,251) with mean 10 years-duration of type 2 diabetes mellitus (T2DM), previous CV events (35%), or significant CV risk, and A1C ≥7.5% were randomized to 'intensive glycemic therapy' or 'standard less aggressive therapy' groups, for a planned 5.6 years follow-up. The primary outcome was the 3-point composite of CV death, nonfatal MI, or non-fatal stroke. ACCORD was halted at 3.5 years because, relative to the standard therapy group, the intensive therapy group experienced a significant 35% increase in the CV death component (p = 0.02) and a significant 22% increase in all-cause mortality (p=0.02); thus, identifying potential harm of intensification of glycemic control in this cohort. Indeed, the annual 3-component atherosclerotic cardiovascular disease (ASCVD) primary outcome occurred in 2.11% of the intensive therapy group and 2.29% of the standard therapy group, consistent with 10-year, 3-component, ASCVD risk for both groups exceeding 20%, or 'very high' risk. The intensive therapy group did experience a non-significant 10% ASCVD risk reduction trend (p=0.16), driven by a significant 24% risk reduction in the nonfatal MI component (p = 0.004), but no significant difference in nonfatal stroke (p=0.74).3
One strongly considered explanation for higher mortality was the demonstration that severe hypoglycemia was three times more frequent in the intensive-therapy group (16%) versus the standard group (5.1%) (p <0.001).3 Furthermore, both arms had higher mortality rate among those with severe hypoglycemia, relative to those without; 6.5% with and 4.7% without, in the intensive arm, and 8.2% with, and 3.6% without, in the standard arm.4 However, paradoxically, despite the 3-fold higher prevalence of severe hypoglycemia in the intensive therapy group, the annual mortality rate associated with individuals with a history of a severe hypoglycemic episode was 2.8% for the intensive arm versus 4.9% for the standard control arm.4-6 Furthermore, among participants with no history of severe hypoglycemia, mortality was higher in the intensive treatment arm (1.3%) versus the standard arm (1.0%). Among the risks in the standard group that might correlate to the increased mortality in ACCORD include advanced age, longer duration diabetes, and higher A1C. Of interest, among older patients with T2DM in ACCORD, hypoglycemia was associated with an increased risk of death from any cause, but particularly among those randomized to standard glycemic treatment.4 Of considerable interest, a post-hoc analysis, before and after adjustment for covariates, demonstrated that a higher average on-treatment A1C was the stronger mortality predictor, compared to the decrease of A1C in the first year, or the A1C obtained in the last interval of follow-up; death in the intensive therapy group increased linearly from 6 through 9% A1C and was greater than the standard therapy group only among those with average A1C was >7%,7 and of all deaths, only one death was adjudicated as definitely related to hypoglycemia.4
In a meta-analysis of several pre-ACCORD studies, when stratified according to the presence of only one abnormal measure associated with cardiac autonomic neuropathy (CAN) (i.e. postural blood pressure (BP), or RR variability, or heart rate variability at rest, or during deep breathing) versus ≥2 abnormalities, the relative mortality risk was 1.20 (p = 0.03) versus 3.45 (p<0.001), respectively.8 The presence of CAN, a downstream effect of chronic long-term hyperglycemia, was investigated as a contributing factor to the higher mortality risk in the intensive glycemia arm of the ACCORD trial. In fully adjusted analyses, participants with baseline CAN were 1.55-2.14 times more likely to die as participants without CAN (p < 0.02), and independent of assignment to intensive therapy or conventional therapy.9 The potential mechanisms of chronic hypoglycemia unawareness, hypoglycemia-associated autonomic failure and severe hypoglycemia-mediated death have been exquisitely described.10-12 Furthermore, susceptibility to cardiac dysrhythmias occurs in those with established ASCVD, diabetes duration, and CAN, and has been strongly associated with increased mortality.9,13,14
The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE),15 ADVANCE study enrolled middle-aged and older adults with type 2 diabetes (n=11,140) with pre-existing microvascular disease (10.4%) or macrovascular disease (32%) or a risk factor for vascular disease. Relative to the ACCORD trial, ADVANCE participants had a 2-year shorter duration of diabetes at 8 years (vs. ACCORD at 10 years), lower baseline A1C at 7.2% (vs. ACCORD at 8.1%), and less patients taking insulin (40.5% in the intensive group and 24.1% in the standard group (versus ACCORD 73% and 58%, respectively). Notably, severe hypoglycemia in ADVANCE occurred much less frequently at 2.7% in the intensive vs. 1.5% in the control, far less then was observed in the ACCORD trial (16%) or the Veterans Affairs Diabetes Trial (VADT) (21%). In ADVANCE, all-cause mortality was reduced by 7% (8.9% in the intensive control group and 9.6% in the standard control group) and CV death was reduced by 12% in the intensive therapy group, both non-significantly.
In the relatively smaller VADT,16 participants (n=1791), mean age 60 years, 11.5 years diabetes duration, with baseline A1C 9.4%, predominantly high-risk, older males (97%); 40% prior CVD events, the primary outcome was a major adverse cardiovascular events (MACE) composite of myocardial infarction (MI), stroke, death from CV causes, heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. At median 5.6-year follow-up, the between-group A1C difference was 1.5%; standard therapy group at A1C 8.4% versus intensive-therapy group at 6.9%. The intensive therapy group had a non-significantly reduced trend of 12% (p=0.14) for the primary outcome and a non-significantly increased trend 7% (p=0.62) in death from any cause. There was an increased incidence of severe hypoglycemia in the intensive treatment group, predicted in both groups by increased duration of diabetes, insulin treatment at baseline, low body mass index (BMI), previous cardiovascular events, and high albumin-to-creatinine ratio.17 Prospective coronary artery calcium (CAC) Agatston scoring done in 301 participants in the VADT, demonstrated that those with CAC score >100 had no significant ASCVD event benefit from intensive glycemic control, while those with CAC score <100 had a 10-fold greater reduction in events with intensive glycemic control,18 consistent with susceptibility to events among patients with known clinical, or subclinical, ASCVD.
Relationship of Severe Hypoglycemia and ASCVD Events
Several studies identified severe hypoglycemia to be one of the strongest predictors of ASCVD events, adverse clinical outcomes, and mortality in those with T2DM.5,17,19,20-25 Several studies and analyses have demonstrated significantly increased risk of ASCVD events in a temporal fashion ranging from shortly after to up to 1.5 years following a single severe hypoglycemia episode.2,10,23,26-29 Participants with diagnosed diabetes (n=1209) from the Atherosclerosis Risk in Communities (ARIC) study, had prospective CV events and deaths captured from 1996 through 2013; severe hypoglycemia was associated with 3-year cumulative congenital heart disease (CHD) (HR 2.02), all-cause mortality (HR 1.73), CV mortality (HR 1.64), and cancer mortality (HR 2.49).29
The sympathoadrenal catecholamine release response during hypoglycemia [Figure 1] may induce dysrhythmias/arrhythmias and increase cardiac workload and serve as mechanistic evidence that links hypoglycemia to cardiovascular risk.23 Hypoglycemia causes a transiently prolonged corrected QT interval and increased QT dispersion.5,25,30 QT prolongation is a strong risk factor for severe ventricular arrhythmias and sudden death.25 When the brain becomes neuroglycopenic and the central autonomic nervous system is stimulated, the sympathoadrenal activation, as the most important part of the counterregulatory response to hypoglycemia,25 leads to increased heart rate, cardiac stroke volume, decreased peripheral resistance and provokes a substantial rise in myocardial contractility and cardiac output.
Hypoglycemic events trigger inflammation with release of C-reactive protein (CRP), IL-6, and vascular endothelial growth factor (VEGF), and induces platelet and neutrophil activation. The prothrombotic effect of low BG levels from catecholamine release, increases blood viscosity and promotes platelet activation/aggregation, leukocyte mobilization and coagulation.24,25 Against a background of endothelial dysfunction and reduced vasodilation; sympathetic activity may be the underlying mechanism leading to hemodynamic changes that cause destabilization of atherosclerotic plaques.31
Any, or all, of these pathophysiological responses may contribute to CV event susceptibility, especially in those individuals with long-standing diabetes, established ASCVD, and cardiac muscle dysfunction. Despite a desirable early attainment and maintenance of euglycemia to prevent acute and chronic complications [Figure 1], one should clearly understand the burden of acute severe hypoglycemia episodes. In addition, in patients with chronic hypoglycemic unawareness, the challenge is incessant and contemporary hypoglycemic episode avoidance strategies, which are critical as an integral component of the management of patients with diabetes; these discussions were beyond the scope of this brief review.
- American Diabetes Association Workgroup on Hypoglycemia. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005;28:1245–49.
- International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017;40:155-57.
- Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59.
- Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD Study. BMJ 2010;340:b4909.
- Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009;94:709-28.
- Bloomgarden, ZT. Cardiovascular disease and glycemic treatment. Diabetes Care 2010;33:e134-e139.
- Riddle MC, Ambrosius WT, Brillon DJ, et al. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33:983-90.
- Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 2003;26:1895-1901.
- Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010;33:1578-84.
- Cryer PE. Death during intensive glycemic therapy of diabetes: mechanisms and implications. Am J Med 2011;124:993-96.
- Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes 2013;62:3570–81.
- Cryer PE. Hypoglycemia-associated autonomic failure in diabetes. Handb Clin Neurol 2013;117:295-307.
- Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007;115:387-97.
- Pop-Busui R, Braffett BH, Zinman B, et al. Cardiovascular autonomic neuropathy and cardiovascular outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Diabetes Care 2017;40:94-100.
- ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
- Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.
- Desouza CV, Bolli GB, Fonseca V. Hyoglycemia, diabetes, and cardiovascular events. Diabetes Care 2010;33:1389-94.
- Reaven PD, Moritz TE, Schwenke DC, et al. Intensive glucose-lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial participants with lower calcified coronary atherosclerosis. Diabetes 2009;58:2642–48.
- Svensson AM, McGuire DK, Abrahamsson P, Dellborg M. Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J 2005;26:1255-61.
- Malmberg K, Rydén L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650-61.
- Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation 2017;136:249-59.
- Goyal A, Mehta SR, Díaz R, et al. Differential clinical outcomes associated with hypoglycemia and hyperglycemia in acute myocardial infarction. Circulation 2009;120:2429-37.
- Yakubovich N, Gerstein HC. Serious cardiovascular outcomes in diabetes: the role of hypoglycemia. Circulation 2011;123:342-48.
- Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013;347:f4533.
- Hanefeld M, Frier BM, Pistrosch F. Hypoglycemia and cardiovascular risk: is there a major link? Diabetes Care 2016;39:S205-S209.
- Pinto DS, Skolnick AH, Kirtane AJ, et al. U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2005;46:178-80.
- Khunti K, Alsifri S, Aronson R, et. al. Rates and predictors of hypoglycemia in 27,585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study. Diabetes Obes Metab 2016;18:907-15.
- Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013;36:1384-95.
- Lee AK, Warren B, Lee CJ, et al. The association of severe hypoglycemia with incident cardiovascular events and mortality in adults with type 2 diabetes. Diabetes Care 2018;41:104-11.
- Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes--the 'dead in bed' syndrome revisited. Diabetologia 2009;52:42-45.
- Hilsted J, Bonde-Petersen F, Nørgaard MB, et al. Haemodynamic changes in insulin-induced hypoglycaemia in normal man. Diabetologia 1984;26:328-32.
Keywords: Diabetes Mellitus, Type 2, Diabetes Mellitus, Hemoglobin A, Gliclazide, Insulin, Blood Glucose, Body Mass Index, Cardiovascular Diseases, Calcium, Creatinine, Risk Factors, Heart Rate, Vascular Endothelial Growth Factor A, Heart Rate, C-Reactive Protein, C-Reactive Protein, Coma, Goals, Blood Viscosity, Vasodilation, Risk Factors, Incidence, Neutrophil Activation, Cardiovascular Diseases, Plaque, Atherosclerotic, Prospective Studies, Hypoglycemia, Hypoglycemic Agents, Stroke Volume, Interleukin-6, Metabolic Syndrome X
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